Pyrrolo[1,2-b]pyridazine derivatives

ABSTRACT

A compound of Formula (I): 
     
       
         
         
             
             
         
       
         
         
           
             pharmaceutically acceptable salts thereof, deuterated analogs thereof, compositions thereof, and methods of treating disease using a compound thereof are disclosed.

CROSS REFERENCE TO RELATED APPLICATION

This Application claims the benefit of U.S. Provisional Application62/718,273 filed on Aug. 13, 2018. The entire contents of theseapplications are incorporated herein by reference in their entirety.

FIELD

The present disclosure relates to novel compounds that are inhibitors ofthe kinase IRAK4. The disclosure also relates to methods for preparingthe compounds and to pharmaceutical compositions comprising suchcompounds.

BACKGROUND

Interleukin-1 receptor-associated kinase-4 (IRAK4) is a serine-threoninekinase which acts as a mediator in interleukin-1/Toll-like receptor(IL-1/TLR) signaling cascades. More particularly, IRAK4 is involved inactivation of adaptor protein myeloid differentiation primary responsegene 88 (MyD88) signaling cascades and is hypothesized to play a role ininflammatory and fibrotic disorders, such as rheumatoid arthritis (RA),inflammatory bowel disease (IBD), gout, Lyme disease, arthritis,psoriasis, pelvic inflammatory disease, systemic lupus erythematosus(SLE), Sjogren's syndrome, viral myocarditis, acute and chronic tissueinjury, non-alcoholic steatohepatitis (NASH), alcoholic hepatitis andkidney disease, including chronic kidney disease and diabetic kidneydisease. In addition, IRAK4 plays a role in certain cancers and ishypothesized to play a role in inflammation associated withgastrointestinal infections, including C. difficile. Signaling throughIL-1R/TLR results in the activation of MyD88 which recruits IRAK4 andIRAK1 to form a signaling complex. This complex then interacts with aseries of kinases, adaptor proteins, and ligases, ultimately resultingin the activation of nuclear factor kappa-light-chain-enhancer ofactivated B cells (NF-κB), activator protein-1 (AP1), cyclicAMP-responsive element-binding protein (CREB) and theinterferon-regulatory factors (IRFs), including IRF5 and IRF7, inducingthe generation of pro-inflammatory cytokines and type I interferons.

Therefore, inhibitors of IRAK4 may be useful in the treatment ofinflammatory and fibrotic disorders, such as rheumatoid arthritis (RA),inflammatory bowel disease (IBD), gout, Lyme disease, arthritis,psoriasis, pelvic inflammatory disease, systemic lupus erythematosus(SLE), Sjogren's syndrome, inflammation associated with gastrointestinalinfections, including C. difficile, viral myocarditis, acute and chronictissue injury, non-alcoholic steatohepatitis (NASH), alcoholic hepatitisand kidney disease, including chronic kidney disease and diabetic kidneydisease. (Joosten, L. A. B et al., TOLL-LIKE RECEPTORS AND CHRONICINFLAMMATION IN RHEUMATIC DISEASES: NEW DEVELOPMENTS, Nat. Rev.Rheumatol., 346|June 2016 12; 344-357 Published online 12 May 2016)(Valaperti, A. et al., INNATE IMMUNE INTERLEUKIN-1 RECEPTOR-ASSOCIATEDKINASE 4 EXACERBATES VIRAL MYOCARDITIS BY REDUCING CCR5⁺CD11b⁺ MONOCYTEMIGRATION AND IMPAIRING INTERFERON PRODUCTION, Circulation,128|SEPTEMBER 2013 14; 1542-1554), as well as Type I interferonopathies,such as Aicardi-Goutibres syndrome, Familial chilblain lupus, andRetinal vasculopathy with cerebral leukodystrophy, (Lee-Kirsch et al.,TYPE I INTERFERONOPATHIES—AN EXPANDING DISEASE SPECTRUM OFIMMUNODYSREGULATION, Semin. Immunopathol. (2015) 37:349-357), (Leaf, I.A. et al., PERICYTE MYD88 AND IRAK4 CONTROL INFLAMMATORY AND FIBROTICRESPONSES TO TISSUE INJURY, The Journal of Clinical Investigation,127|January 2017 1; 321-334), (Seki, E. et al., TLR4 ENHANCES TGF-βSIGNALING AND HEPATIC FIBROSIS, Nature Medicine, 13|NOVEMBER 2007 11;1324-1332), (Garcia-Martinez, I. et al., HEPATOCYTE MITOCHONDRIAL DNADRIVES NONALCHOLIC STEATOHEPATITIS BY ACTIVATION OF TLR9, The Journal ofClinical Investigation, 126|March 2016 3; 859-864).

In addition, certain cancers, including lymphomas, may contain one ormore mutations in the MYD88 adaptor protein, leading to a constitutivelyactive signaling cascade that may promote survival of tumor cells.(Kelly et al., IRAK4 inhibitors for autoimmunity and lymphoma, J. Exp.Med. 2015 Vol. 212 No. 13 2189-2201)

Therefore, an inhibitor of IRAK4 may be useful in the treatment ofcancers, including lymphomas.

There are currently no approved IRAK4 inhibiting pharmaceuticals.Therefore, it would be useful to provide an IRAK4 inhibiting compoundwith properties suitable for administration as a pharmaceutical agent toa mammal, particularly a human. Considerations for selecting apharmaceutical compound are multifactorial. Compound characteristicsincluding on-target potency, pharmacokinetics, pKa, solubility,stability (e.g., metabolic stability) and off-target liabilities arefrequently profiled.

WO2016210034, WO2016210036, WO2015150995, WO2016127024, and WO2016210037recite compounds said to be useful as IRAK4 inhibitors.

SUMMARY OF THE INVENTION

Provided herein are compounds and pharmaceutical compositions useful asinhibitors of IRAK4. Some compounds of the disclosure may find use inpharmaceutical compositions, together with at least one pharmaceuticallyacceptable excipient, for treating a subject in need thereof. Compoundsof the present disclosure also have been found to inhibit production ofpro-inflammatory cytokines TNFα, IL-6, IL-1β, IL-8, IL-12, IL-23 andtype I interferons IFNα and IFNβ, all of which are mediators ofinflammation and the immune response. The disclosure also providescompositions, including pharmaceutical compositions, kits that includethe compounds, and methods of using and making the compounds.

In one embodiment of the disclosure, there is provided a compound ofFormula (I):

wherein Y is selected from: —H, —F, —Cl, —Br, —CN, —CF₃, —CF₂H, —OH, and—OCH₃;

R¹ is selected from C₃₋₁₀ cycloalkyl optionally substituted with X¹ and4-12 membered heterocyclyl optionally substituted with X¹;

wherein each X¹ is independently oxo, halo, —NO₂, —N₃, —CN, C₁₋₉ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈ haloalkyl, —O—R¹²,—C(O)—R¹², —C(O)O—R¹², —C(O)—N(R¹²)(R¹²), —N(R¹²)(R¹²), —N(R¹²)₂(R¹²)⁺,—N(R¹²)C(O)—R¹², —N(R¹²)C(O)O—R¹², or —N(R¹²)C(O)N(R¹²)(R¹²);

“Het” is selected from 5-10 membered heteroaryl optionally substitutedwith X² or 4-12 membered heterocyclyl optionally substituted with X²;

wherein each X² is selected from oxo, halo, N₃, —CN, C₁₋₉ alkyl, C₃₋₆cycloalkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈ haloalkyl,4-12 membered heterocyclyl —O—R¹², C₁₋₆ cyano alkyl, C₁₋₆ alkyl ether,—OC(O)R¹², —OC(O)OR¹², —OC(O)—N(R¹²)(R¹²), and —C(O)N(R¹²)(R¹²), whereinany alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, or heterocyclyl isoptionally substituted with Z^(1a);

R² is selected from:

a) C₁₋₁₀ alkyl optionally substituted with Z¹;

b) C₃₋₁₀ cycloalkyl optionally substituted with Z¹;

c) 5-10 membered heteroaryl optionally substituted with Z¹;

d) C₆₋₁₀ aryl optionally substituted with Z¹; and

e) 4-12 membered heterocyclyl optionally substituted with Z¹;

wherein Z¹ is independently oxo, halo, —NO₂, —N₃, —CN, C₁₋₉ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈ haloalkyl, aryl,heteroaryl, heterocyclyl, —O—R¹², —C(O)—R¹², —C(O)O—R¹²,—C(O)—N(R¹²)(R¹²), —N(R¹²)(R¹²), —N(R¹²)₂(R¹²)⁺, —N(R¹²)C(O)—R¹²,—N(R¹²)C(O)O—R¹², —N(R¹²)C(O)N(R¹²)(R¹²), —N(R¹²)S(O)₂(R¹²),—NR¹²S(O)₂N(R¹²)(R¹²), —NR¹²S(O)₂O(R¹²), —OC(O)R¹², —OC(O)OR¹²,—OC(O)—N(R¹²)(R¹²), —Si(R¹²)₃, —S—R¹², —S(O)R¹², —S(O)(NH)R¹², —S(O)₂R¹²or —S(O)₂N(R¹²)(R¹²); wherein any alkyl, alkenyl, alkynyl, cycloalkyl,haloalkyl, aryl, heteroaryl or heterocyclyl is optionally substitutedwith Z^(1a);

each Z^(1a) is independently oxo, halo, —NO₂, —CN, —N₃, C₁₋₉ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈ haloalkyl, aryl,heteroaryl, heterocyclyl, —O—R¹², —C(O)R¹², —C(O)O—R¹²,—C(O)N(R¹²)(R¹²), —N(R¹²)(R¹²), —N(R¹²)₂(R¹²)⁺, —N(R¹²)—C(O)R¹²,—N(R¹²)C(O)O(R¹²), —N(R¹²)C(O)N(R¹²)(R¹²), —N(R¹²)S(O)₂(R¹²),—N(R¹²)S(O)₂—N(R¹²)(R¹²), —N(R¹²)S(O)₂O(R¹²), —OC(O)R¹², —OC(O)OR¹²,—OC(O)—N(R¹²)(R¹²), —Si(R¹²)₃, —S—R¹², —S(O)R¹², —S(O)(NH)R¹², —S(O)₂R¹²or —S(O)₂N(R¹²)(R¹²);

wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl,heteroaryl or heterocyclyl is optionally substituted with Z^(1b);

each R¹² is independently H, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₅ cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl orheterocyclyl is optionally substituted with Z^(1a);

each Z^(1b) is independently oxo, hydroxy, halo, —NO₂, —N₃, —CN, C₁₋₉alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈ haloalkyl,aryl, heteroaryl, heterocyclyl, —O(C₁₋₉ alkyl), —O(C₂₋₆ alkenyl),—O(C₂₋₆ alkynyl), —O(C₃₋₁₅ cycloalkyl), —O(C₁₋₈ haloalkyl), —O(aryl),—O(heteroaryl), —O(heterocyclyl), —NH₂, —NH(C₁₋₉ alkyl), —NH(C₂₋₆alkenyl), —NH(C₂₋₆ alkynyl), —NH(C₃₋₁₅ cycloalkyl), —NH(C₁₋₈ haloalkyl),—NH(aryl), —NH(heteroaryl), —NH(heterocyclyl), —N(C₁₋₉ alkyl)₂, —N(C₃₋₁₅cycloalkyl)₂, —N(C₂₋₆ alkenyl)₂, —N(C₂₋₆ alkynyl)₂, —N(C₃₋₁₅cycloalkyl)₂, —N(C₁₋₈ haloalkyl)₂, —N(aryl)₂, —N(heteroaryl)₂,—N(heterocyclyl)₂, —N(C₁₋₉ alkyl)(C₃₋₁₅ cycloalkyl), —N(C₁₋₉ alkyl)(C₂₋₆alkenyl), —N(C₁₋₉ alkyl)(C₂₋₆ alkynyl), —N(C₁₋₉ alkyl)(C₃₋₁₅cycloalkyl), —N(C₁₋₉ alkyl)(C₁₋₈ haloalkyl), —N(C₁₋₉ alkyl)(aryl),—N(C₁₋₉ alkyl)(heteroaryl), —N(C₁₋₉ alkyl)(heterocyclyl), —C(O)(C₁₋₉alkyl), —C(O)(C₂₋₆ alkenyl), —C(O)(C₂₋₆ alkynyl), —C(O)(C₃₋₁₅cycloalkyl), —C(O)(C₁₋₈ haloalkyl), —C(O)(aryl), —C(O)(heteroaryl),—C(O)(heterocyclyl), —C(O)O(C₁₋₉ alkyl), —C(O)O(C₂₋₆ alkenyl),—C(O)O(C₂₋₆ alkynyl), —C(O)O(C₃₋₁₅ cycloalkyl), —C(O)O(C₁₋₈ haloalkyl),—C(O)O(aryl), —C(O)O(heteroaryl), —C(O)O(heterocyclyl), —C(O)NH₂,—C(O)NH(C₁₋₉ alkyl), —C(O)NH(C₂₋₆ alkenyl), —C(O)NH(C₂₋₆ alkynyl),—C(O)NH(C₃₋₁₅ cycloalkyl), —C(O)NH(C₁₋₈ haloalkyl), —C(O)NH(aryl),—C(O)NH(heteroaryl), —C(O)NH(heterocyclyl), —C(O)N(C₁₋₉ alkyl)₂,—C(O)N(C₃₋₁₅ cycloalkyl)₂, —C(O)N(C₂₋₆ alkenyl)₂, —C(O)N(C₂₋₆ alkynyl)₂,—C(O)N(C₃₋₁₅ cycloalkyl)₂, —C(O)N(C₁₋₈ haloalkyl)₂, —C(O)N(aryl)₂,—C(O)N(heteroaryl)₂, —C(O)N(heterocyclyl)₂, —NHC(O)(C₁₋₉ alkyl),—NHC(O)(C₂₋₆ alkenyl), —NHC(O)(C₂₋₆ alkynyl), —NHC(O)(C₃₋₁₅ cycloalkyl),—NHC(O)(C₁₋₈ haloalkyl), —NHC(O)(aryl), —NHC(O)(heteroaryl),—NHC(O)(heterocyclyl), —NHC(O)O(C₁₋₉ alkyl), —NHC(O)O(C₂₋₆ alkenyl),—NHC(O)O(C₂₋₆ alkynyl), —NHC(O)O(C₃₋₁₅ cycloalkyl), —NHC(O)O(C₁₋₈haloalkyl), —NHC(O)O(aryl), —NHC(O)O(heteroaryl),—NHC(O)O(heterocyclyl), —NHC(O)NH(C₁₋₉ alkyl), —NHC(O)NH(C₂₋₆ alkenyl),—NHC(O)NH(C₂₋₆ alkynyl), —NHC(O)NH(C₃₋₁₅ cycloalkyl), —NHC(O)NH(C₁₋₈haloalkyl), —NHC(O)NH(aryl), —NHC(O)NH(heteroaryl),—NHC(O)NH(heterocyclyl), —SH, —S(C₁₋₉ alkyl), —S(C₂₋₆ alkenyl), —S(C₂₋₆alkynyl), —S(C₃₋₁₅ cycloalkyl), —S(C₁₋₈ haloalkyl), —S(aryl),—S(heteroaryl), —S(heterocyclyl), —NHS(O)(C₁₋₉ alkyl), —N(C₁₋₉alkyl)(S(O)(C₁₋₉ alkyl), —S(O)N(C₁₋₉ alkyl)₂, —S(O)(C₁₋₉ alkyl),—S(O)(NH)(C₁₋₉ alkyl), —S(O)(C₂₋₆ alkenyl), —S(O)(C₂₋₆ alkynyl),—S(O)(C₃₋₁₅ cycloalkyl), —S(O)(C₁ s haloalkyl), —S(O)(aryl),—S(O)(heteroaryl), —S(O)(heterocyclyl), —S(O)₂(C₁₋₉ alkyl), —S(O)₂(C₂₋₆alkenyl), —S(O)₂(C₂₋₆ alkynyl), —S(O)₂(C₃₋₁₅ cycloalkyl), —S(O)₂(C₁₋₈haloalkyl), —S(O)₂(aryl), —S(O)₂(heteroaryl), —S(O)₂(heterocyclyl),—S(O)₂NH(C₁₋₉ alkyl), or —S(O)₂N(C₁₋₉ alkyl)₂; wherein any alkyl,cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substitutedwith one or more halo, C₁₋₉ alkyl, C₁₋₈ haloalkyl, —OH, —NH₂, —NH(C₁₋₉alkyl), —NH(C₃₋₁₅ cycloalkyl), —NH(C₁₋₈ haloalkyl), —NH(aryl),—NH(heteroaryl), —NH(heterocyclyl), —N(C₁₋₉ alkyl)₂, —N(C₃₋₁₅cycloalkyl)₂, —NHC(O)(C₃₋₁₅ cycloalkyl), —NHC(O)(C₁₋₈ haloalkyl),—NHC(O)(aryl), —NHC(O)(heteroaryl), —NHC(O)(heterocyclyl), —NHC(O)O(C₁₋₉alkyl), —NHC(O)O(C₂₋₆ alkynyl), —NHC(O)O(C₃₋₁₅ cycloalkyl),—NHC(O)O(C₁₋₈ haloalkyl), —NHC(O)O(aryl), —NHC(O)O(heteroaryl),—NHC(O)O(heterocyclyl), —NHC(O)NH(C₁₋₉ alkyl), —S(O)(NH)(C₁₋₉ alkyl),S(O)₂(C₁₋₉ alkyl), —S(O)₂(C₃₋₁₅ cycloalkyl), —S(O)₂(C₁₋₈ haloalkyl),—S(O)₂(aryl), —S(O)₂(heteroaryl), —S(O)₂(heterocyclyl), —S(O)₂NH(C₁₋₉alkyl), —S(O)₂N(C₁₋₉ alkyl)₂, —O(C₃₋₁₅ cycloalkyl), —O(C₁₋₈ haloalkyl),—O(aryl), —O(heteroaryl), —O(heterocyclyl), or —O(C₁₋₉ alkyl);

or a pharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, or deuterated analog thereof.

In one embodiment, R¹ is C₃₋₁₀ cycloalkyl optionally substituted withX¹.

In another embodiment, R¹ is selected from cyclohexyl andbicyclo[2.2.2]octane.

In another embodiment, R¹ is 4-12 membered heterocyclyl optionallysubstituted with X¹.

In another embodiment, R¹ is tetrahydropyran.

In another embodiment, R¹ is oxabicyclo[2.2.2]octane.

In one embodiment, “Het” is selected from:

In another embodiment, “Het” is:

In some embodiments, “Het” is substituted with X².

In one embodiment, X² is halo, CN, C₁₋₉ alkyl, C₃₋₆ cycloalkyl. C₃₋₁₅cycloalkyl, C₁₋₈ haloalkyl, 4-12 membered heterocyclyl, —O—R¹², C₁₋₆cyano alkyl, C₁₋₆ alkyl ether, —OC(O)R², —OC(O)OR¹², and—C(O)—N(R¹²)(R¹²).

In an embodiment, X² is selected from —F, CN, C₁₋₄ alkyl, C₁₋₈haloalkyl, C₃₋₄ cycloalkyl, and C₁₋₃cyanoalkyl.

In another embodiment, X² is selected from methyl, ethyl, —CHF₂, —CF₃,cyclopropyl, —CH₂CHF₂, and —CH₂CF₃.

In another embodiment, X² is —CHF₂.

In another embodiment, R² is C₁₋₁₀ alkyl optionally substituted with Z¹.

In another embodiment, R² is C₁₋₁₀ alkyl optionally substituted with oneor more —F or —OH, or combinations of F and OH.

In another embodiment, R² is C₃₋₁₀ cycloalkyl optionally substitutedwith Z¹.

In another embodiment, R² is C₃₋₈ cycloalkyl optionally substituted with—OH, —N(R¹²)C(O)(R¹²), —N(R¹²)C(O)O(R¹²), or —C(O)N(R¹²)(R¹²).

In an embodiment, X¹ is F.

In an embodiment, Y is CN.

In other embodiments, the disclosure provides a compound of Formula(Ia):

wherein,

R¹ is selected from C₃₋₁₀ cycloalkyl optionally substituted with X¹ and4-12 membered heterocyclyl optionally substituted with X¹;

wherein each X¹ is independently oxo, halo, —CN, C₁₋₉ alkyl, and C₃₋₁₅cycloalkyl;

“Het” is selected from 5-10 membered heteroaryl optionally substitutedwith X² and 4-12 membered heterocyclyl optionally substituted with X²;

wherein each X² is selected from oxo, halo, N₃, —CN, C₁₋₉ alkyl, C₃₋₆cycloalkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈ haloalkyl,4-12 membered heterocyclyl —O—R¹², C₁₋₆ cyano alkyl, C₁₋₆ alkyl ether,—OC(O)R¹², —OC(O)OR¹², —OC(O)—N(R¹²)(R¹²), and —C(O)N(R¹²)(R¹²), whereinany alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, or heterocyclyl isoptionally substituted with Z^(1a);

each Z^(1a) is independently oxo, halo, —NO₂, —CN, —N₃, C₁₋₉ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈ haloalkyl, aryl,heteroaryl, heterocyclyl, —O—R¹², —C(O)R¹², —C(O)O—R¹²,—C(O)N(R¹²)(R¹²), —N(R¹²)(R¹²), —N(R¹²)₂(R¹²)⁺, —N(R¹²)—C(O)R¹²,—N(R¹²)C(O)O(R¹²), —N(R¹²)C(O)N(R¹²)(R¹²), —N(R¹²)S(O)₂(R¹²),—N(R¹²)S(O)₂—N(R¹²)(R¹²), —N(R¹²)S(O)₂O(R¹²), —OC(O)R¹², —OC(O)OR¹²,—OC(O)—N(R¹²)(R¹²), —Si(R¹²)₃, —S—R¹², —S(O)R¹², —S(O)(NH)R¹², —S(O)₂R¹²or —S(O)₂N(R¹²)(R¹²);

wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl,heteroaryl or heterocyclyl is optionally substituted with Z^(1b);

each R¹² is independently H, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₅ cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl orheterocyclyl is optionally substituted with Z^(1a);

each Z^(1b) is independently oxo, hydroxy, halo, —NO₂, —N₃, —CN, C₁₋₉alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈ haloalkyl,aryl, heteroaryl, heterocyclyl, —O(C₁₋₉ alkyl), —O(C₂₋₆ alkenyl),—O(C₂₋₆ alkynyl), —O(C₃₋₁₅ cycloalkyl), —O(C₁₋₈ haloalkyl), —O(aryl),—O(heteroaryl), —O(heterocyclyl), —NH₂, —NH(C₁₋₉ alkyl), —NH(C₂₋₆alkenyl), —NH(C₂₋₆ alkynyl), —NH(C₃₋₁₅ cycloalkyl), —NH(C₁₋₈ haloalkyl),—NH(aryl), —NH(heteroaryl), —NH(heterocyclyl), —N(C₁₋₉ alkyl)₂, —N(C₃₋₁₅cycloalkyl)₂, —N(C₂₋₆ alkenyl)₂, —N(C₂₋₆ alkynyl)₂, —N(C₃₋₁₅cycloalkyl)₂, —N(C₁₋₈ haloalkyl)₂, —N(aryl)₂, —N(heteroaryl)₂,—N(heterocyclyl)₂, —N(C₁₋₉ alkyl)(C₃₋₁₅ cycloalkyl), —N(C₁₋₉ alkyl)(C₂₋₆alkenyl), —N(C₁₋₉ alkyl)(C₂₋₆ alkynyl), —N(C₁₋₉ alkyl)(C₃₋₁₅cycloalkyl), —N(C₁₋₉ alkyl)(C₁₋₈ haloalkyl), —N(C₁₋₉ alkyl)(aryl),—N(C₁₋₉ alkyl)(heteroaryl), —N(C₁₋₉ alkyl)(heterocyclyl), —C(O)(C₁₋₉alkyl), —C(O)(C₂₋₆ alkenyl), —C(O)(C₂₋₆ alkynyl), —C(O)(C₃₋₁₅cycloalkyl), —C(O)(C₁₋₈ haloalkyl), —C(O)(aryl), —C(O)(heteroaryl),—C(O)(heterocyclyl), —C(O)O(C₁₋₉ alkyl), —C(O)O(C₂₋₆ alkenyl),—C(O)O(C₂₋₆ alkynyl), —C(O)O(C₃₋₁₅ cycloalkyl), —C(O)O(C₁₋₈ haloalkyl),—C(O)O(aryl), —C(O)O(heteroaryl), —C(O)O(heterocyclyl), —C(O)NH₂,—C(O)NH(C₁₋₉ alkyl), —C(O)NH(C₂₋₆ alkenyl), —C(O)NH(C₂₋₆ alkynyl),—C(O)NH(C₃₋₁₅ cycloalkyl), —C(O)NH(C₁ s haloalkyl), —C(O)NH(aryl),—C(O)NH(heteroaryl), —C(O)NH(heterocyclyl), —C(O)N(C₁₋₉ alkyl)₂,—C(O)N(C₃₋₁₅ cycloalkyl)₂, —C(O)N(C₂₋₆ alkenyl)₂, —C(O)N(C₂₋₆ alkynyl)₂,—C(O)N(C₃₋₁₅ cycloalkyl)₂, —C(O)N(C₁₋₈ haloalkyl)₂, —C(O)N(aryl)₂,—C(O)N(heteroaryl)₂, —C(O)N(heterocyclyl)₂, —NHC(O)(C₁₋₉ alkyl),—NHC(O)(C₂₋₆ alkenyl), —NHC(O)(C₂₋₆ alkynyl), —NHC(O)(C₃₋₁₅ cycloalkyl),—NHC(O)(C₁₋₈ haloalkyl), —NHC(O)(aryl), —NHC(O)(heteroaryl),—NHC(O)(heterocyclyl), —NHC(O)O(C₁₋₉ alkyl), —NHC(O)O(C₂₋₆ alkenyl),—NHC(O)O(C₂₋₆ alkynyl), —NHC(O)O(C₃₋₁₅ cycloalkyl), —NHC(O)O(C₁₋₈haloalkyl), —NHC(O)O(aryl), —NHC(O)O(heteroaryl),—NHC(O)O(heterocyclyl), —NHC(O)NH(C₁₋₉ alkyl), —NHC(O)NH(C₂₋₆ alkenyl),—NHC(O)NH(C₂₋₆ alkynyl), —NHC(O)NH(C₃₋₁₅ cycloalkyl), —NHC(O)NH(C₁₋₈haloalkyl), —NHC(O)NH(aryl), —NHC(O)NH(heteroaryl),—NHC(O)NH(heterocyclyl), —SH, —S(C₁₋₉ alkyl), —S(C₂₋₆ alkenyl), —S(C₂₋₆alkynyl), —S(C₃₋₁₅ cycloalkyl), —S(C₁₋₈ haloalkyl), —S(aryl),—S(heteroaryl), —S(heterocyclyl), —NHS(O)(C₁₋₉ alkyl), —N(C₁₋₉alkyl)(S(O)(C₁₋₉ alkyl), —S(O)N(C₁₋₉ alkyl)₂, —S(O)(C₁₋₉ alkyl),—S(O)(NH)(C₁₋₉ alkyl), —S(O)(C₂₋₆ alkenyl), —S(O)(C₂₋₆ alkynyl),—S(O)(C₃₋₁₅ cycloalkyl), —S(O)(C₁₋₈ haloalkyl), —S(O)(aryl),—S(O)(heteroaryl), —S(O)(heterocyclyl), —S(O)₂(C₁₋₉ alkyl), —S(O)₂(C₂₋₆alkenyl), —S(O)₂(C₂₋₆ alkynyl), —S(O)₂(C₃₋₁₅ cycloalkyl), —S(O)₂(C₁₋₈haloalkyl), —S(O)₂(aryl), —S(O)₂(heteroaryl), —S(O)₂(heterocyclyl),—S(O)₂NH(C₁₋₉ alkyl), or —S(O)₂N(C₁₋₉ alkyl)₂; wherein any alkyl,cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substitutedwith one or more halo, C₁₋₉ alkyl, Cis haloalkyl, —OH, —NH₂,—NH(C₁₋₉alkyl), —NH(C₃₋₁₅ cycloalkyl), —NH(C₁₋₈ haloalkyl), —NH(aryl),—NH(heteroaryl), —NH(heterocyclyl), —N(C₁₋₉ alkyl)₂, —N(C₃₋₁₅cycloalkyl)₂, —NHC(O)(C₃₋₁₅ cycloalkyl), —NHC(O)(C₁₋₈ haloalkyl),—NHC(O)(aryl), —NHC(O)(heteroaryl), —NHC(O)(heterocyclyl), —NHC(O)O(C₁₋₉alkyl), —NHC(O)O(C₂₋₆ alkynyl), —NHC(O)O(C₃₋₁₅ cycloalkyl),—NHC(O)O(C₁₋₈ haloalkyl), —NHC(O)O(aryl), —NHC(O)O(heteroaryl),—NHC(O)O(heterocyclyl), —NHC(O)NH(C₁₋₉ alkyl), —S(O)(NH)(C₁₋₉ alkyl),S(O)₂(C₁₋₉ alkyl), —S(O)₂(C₃₋₁₅ cycloalkyl), —S(O)₂(C₁₋₈ haloalkyl),—S(O)₂(aryl), —S(O)₂(heteroaryl), —S(O)₂(heterocyclyl), —S(O)₂NH(C₁₋₉alkyl), —S(O)₂N(C₁₋₉ alkyl)₂, —O(C₃₋₁₅ cycloalkyl), —O(C₁₋₈ haloalkyl),—O(aryl), —O(heteroaryl), —O(heterocyclyl), or —O(C₁₋₉ alkyl);

or a pharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, or deuterated analog thereof.

Also provided in the disclosure are pharmaceutical compositionscomprising a compound of Formula (I) or (Ia) or a pharmaceuticallyacceptable salt, stereoisomer, mixture of stereoisomers or deuteratedanalog thereof, together with a pharmaceutically acceptable carrier.

The disclosure also provides methods of treating inflammatory conditionsin a patient in need of treatment. The method comprises administering acompound of Formula (I) or (Ia) as described above to said patient in atherapeutically effective amount. In another embodiment, the methodcomprises administering a composition comprising a therapeuticallyeffective compound of Formula (I) or (Ia) to a patient in need thereof.

In some embodiments, the inflammatory condition is selected fromInflammatory Bowel Disease (IBD), Systemic Lupus Erythematosus (SLE),Psoriasis or Rheumatoid Arthritis.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The following description sets forth exemplary methods, parameters andthe like. It should be recognized, however, that such description is notintended as a limitation on the scope of the present disclosure but isinstead provided as a description of exemplary embodiments.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —C(O)NH₂is attached through the carbon atom. A dash at the front or end of achemical group is a matter of convenience; chemical groups may bedepicted with or without one or more dashes without losing theirordinary meaning. A wavy line drawn through a line in a structureindicates a point of attachment of a group. Unless chemically orstructurally required, no directionality is indicated or implied by theorder in which a chemical group is written or named.

The prefix “C_(u)-v” indicates that the following group has from u to vcarbon atoms. For example, “C₁₋₆ alkyl” indicates that the alkyl grouphas from 1 to 6 carbon atoms.

Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse. In certain embodiments, the term “about” includes the indicatedamount ±10%. In other embodiments, the term “about” includes theindicated amount ±5%. In certain other embodiments, the term “about”includes the indicated amount ±1%. Also, to the term “about X” includesdescription of “X”. Also, the singular forms “a” and “the” includeplural references unless the context clearly dictates otherwise. Thus,e.g., reference to “the compound” includes a plurality of such compoundsand reference to “the assay” includes reference to one or more assaysand equivalents thereof known to those skilled in the art.

“Alkyl” refers to an unbranched or branched saturated hydrocarbon chain.As used herein, alkyl has 1 to 20 carbon atoms (i.e., C₁₋₂₀ alkyl), 1 to8 carbon atoms (i.e., C₁₋₈ alkyl), 1 to 6 carbon atoms (i.e., C₁₋₆alkyl), or 1 to 4 carbon atoms (i.e., C₁₋₄ alkyl). Examples of alkylgroups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl,iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl,2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having aspecific number of carbons is named by chemical name or identified bymolecular formula, all positional isomers having that number of carbonsmay be encompassed; thus, for example, “butyl” includes n-butyl (i.e.,—(CH₂)₃CH₃), sec-butyl (i.e., —CH(CH₃)CH₂CH₃), isobutyl (i.e.,—CH₂CH(CH₃)₂) and tert-butyl (i.e., —C(CH₃)₃); and “propyl” includesn-propyl (i.e., —(CH₂)₂CH₃) and isopropyl (i.e., —CH(CH₃)₂).

“Alkenyl” refers to an alkyl group containing at least one carbon-carbondouble bond and having from 2 to 20 carbon atoms (i.e., C₂₋₂₀ alkenyl),2 to 8 carbon atoms (i.e., C₂₋₈ alkenyl), 2 to 6 carbon atoms (i.e.,C₂₋₆ alkenyl), or 2 to 4 carbon atoms (i.e., C₂₋₄ alkenyl). Examples ofalkenyl groups include ethenyl, propenyl, butadienyl (including1,2-butadienyl and 1,3-butadienyl).

“Alkynyl” refers to an alkyl group containing at least one carbon-carbontriple bond and having from 2 to 20 carbon atoms (i.e., C₂₋₂₀ alkynyl),2 to 8 carbon atoms (i.e., C₂₋₈ alkynyl), 2 to 6 carbon atoms (i.e.,C₂₋₆ alkynyl), or 2 to 4 carbon atoms (i.e., C₂₋₄ alkynyl). The term“alkynyl” also includes those groups having one triple bond and onedouble bond.

“Alkoxy” refers to the group “alkyl-O—”. Examples of alkoxy groupsinclude methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy,sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

“Haloalkoxy” refers to an alkoxy group as defined above, wherein one ormore hydrogen atoms are replaced by a halogen.

“Alkylthio” refers to the group “alkyl-S—”.

“Amino” refers to the group —NR^(y)R^(y) wherein each R^(y) isindependently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl or heteroaryl, each ofwhich is optionally substituted, as defined herein.

“Aryl” refers to an aromatic carbocyclic group having a single ring(e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic)including fused systems. As used herein, aryl has 6 to 20 ring carbonatoms (i.e., C₆₋₂₀ aryl), 6 to 12 carbon ring atoms (i.e., C₆₋₁₂ aryl),or 6 to 10 carbon ring atoms (i.e., C₆₋₁₀ aryl). Examples of aryl groupsinclude phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, doesnot encompass or overlap in any way with heteroaryl defined below. Ifone or more aryl groups are fused with a heteroaryl, the resulting ringsystem is heteroaryl. If one or more aryl groups are fused with aheterocyclyl, the resulting ring system is heterocyclyl.

“Cyano” refers to the group —CN.

“Keto” or “oxo” refers to a group ═O.

“Carbamoyl” refers to both an “O-carbamoyl” group which refers to thegroup —O—C(O)NR^(y)R^(z) and an “N-carbamoyl” group which refers to thegroup —NR^(y)C(O)OR^(z), wherein R^(y) and R^(z) are independentlyselected from the group consisting of hydrogen, alkyl, aryl, haloalkyl,or heteroaryl; each of which may be optionally substituted.

“Carboxyl” refers to —C(O)OH.

“Ester” refers to both —OC(O)R and —C(O)OR, wherein R is a substituent;each of which may be optionally substituted, as defined herein.

“Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkylgroup having a single ring or multiple rings including fused, bridged,and spiro ring systems. The term “cycloalkyl” includes cycloalkenylgroups (i.e., the cyclic group having at least one double bond). As usedherein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C₃₋₂₀cycloalkyl), 3 to 12 ring carbon atoms (i.e., C₃₋₁₂ cycloalkyl), 3 to 10ring carbon atoms (i.e., C₃₋₁₀ cycloalkyl), 3 to 8 ring carbon atoms(i.e., C₃₋₈ cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C₃₋₆cycloalkyl). Examples of cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl.

“Halogen” or “halo” includes fluoro, chloro, bromo, and iodo.“Haloalkyl” refers to an unbranched or branched alkyl group as definedabove, wherein one or more hydrogen atoms are replaced by a halogen. Forexample, where a residue is substituted with more than one halogen, itmay be referred to by using a prefix corresponding to the number ofhalogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkylsubstituted with two (“di”) or three (“tri”) halo groups, which may be,but are not necessarily, the same halogen. Examples of haloalkyl includedifluoromethyl (—CHF₂) and trifluoromethyl (—CF₃).

“Heteroalkyl” refers to an alkyl group in which one or more of thecarbon atoms (and any associated hydrogen atoms) are each independentlyreplaced with the same or different heteroatomic group. The term“heteroalkyl” includes unbranched or branched saturated chain havingcarbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may beindependently replaced with the same or different heteroatomic group.Heteroatomic groups include, but are not limited to, —NR—, —O—, —S—,—S(O)—, —S(O)₂—, and the like, where R is H, alkyl, aryl, cycloalkyl,heteroalkyl, heteroaryl or heterocyclyl, each of which may be optionallysubstituted. Examples of heteroalkyl groups include —OCH₃, —CH₂OCH₃,—SCH₃, —CH₂SCH₃, —NRCH₃, and —CH₂NRCH₃, where R is hydrogen, alkyl,aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may beoptionally substituted. As used herein, heteroalkyl include 1 to 10carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

“Heteroaryl” refers to an aromatic group having a single ring, multiplerings, or multiple fused rings, with one or more ring heteroatomsindependently selected from nitrogen, oxygen, and sulfur. As usedherein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C₁₋₂₀heteroaryl), 3 to 12 ring carbon atoms (i.e., C₃₋₁₂ heteroaryl), or 3 to8 carbon ring atoms (i.e., C₃₋₈ heteroaryl); and 1 to 5 heteroatoms, 1to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1ring heteroatom independently selected from nitrogen, oxygen, andsulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl,pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Examples of thefused-heteroaryl rings include, but are not limited to,benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl,indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, andimidazo[1,5-a]pyridinyl, where the heteroaryl can be bound via eitherring of the fused system. Any aromatic ring, having a single or multiplefused rings, containing at least one heteroatom, is considered aheteroaryl regardless of the attachment to the remainder of the molecule(i.e., through any one of the fused rings). Heteroaryl does notencompass or overlap with aryl as defined above.

“Heterocyclyl” refers to a saturated or unsaturated cyclic alkyl group,with one or more ring heteroatoms independently selected from nitrogen,oxygen and sulfur. The term “heterocyclyl” includes heterocycloalkenylgroups (i.e., the heterocyclyl group having at least one double bond),bicyclic heterocyclyl groups, bridged-heterocyclyl groups,fused-heterocyclyl groups, and spiro-heterocyclyl groups. A heterocyclylmay be a single ring or multiple rings wherein the multiple rings may befused, bridged, or spiro. Any non-aromatic ring containing at least oneheteroatom is considered a heterocyclyl, regardless of the attachment(i.e., can be bound through a carbon atom or a heteroatom). Further, theterm heterocyclyl is intended to encompass any non-aromatic ringcontaining at least one heteroatom, which ring may be fused to an arylor heteroaryl ring, regardless of the attachment to the remainder of themolecule. As used herein, heterocyclyl has 2 to 20 ring atoms (i.e.,4-20 membered heterocyclyl), 2 to ring atoms (i.e., 4-12 memberedheterocyclyl), 4 to 10 ring atoms (i.e., 4-10 membered heterocyclyl), 4to 8 ring atoms (i.e., 4-8 membered heterocyclyl), or 4 to 6 ring carbonatoms (i.e., 4-6 membered heterocyclyl); having 1 to 5 ring heteroatoms,1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ringheteroatoms, or 1 ring heteroatom independently selected from nitrogen,sulfur or oxygen. A heterocyclyl may contain one or more oxo and/orthioxo groups. Examples of heterocyclyl groups include pyrrolidinyl,piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, azetidinyl,morpholinyl, thiomorpholinyl, 4-7 membered sultam, 4-7 membered cycliccarbamate, 4-7 membered cyclic carbonate, 4-7 membered cyclic sulfideand morpholinyl. As used herein, the term “bridged-heterocyclyl” refersto a four- to ten-membered cyclic moiety connected at two non-adjacentatoms of the heterocyclyl with one or more (e.g., 1 or 2) four- toten-membered cyclic moiety having at least one heteroatom where eachheteroatom is independently selected from nitrogen, oxygen, and sulfur.As used herein, bridged-heterocyclyl includes bicyclic and tricyclicring systems. Also used herein, the term “spiro-heterocyclyl” refers toa ring system in which a three- to ten-membered heterocyclyl has one ormore additional ring, wherein the one or more additional ring is three-to ten-membered cycloalkyl or three- to ten-membered heterocyclyl, wherea single atom of the one or more additional ring is also an atom of thethree- to ten-membered heterocyclyl. Examples of the spiro-heterocyclylrings include bicyclic and tricyclic ring systems, such as2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and6-oxa-1-azaspiro[3.3]heptanyl. Examples of the fused-heterocyclyl ringsinclude, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl,1-oxo-1,2,3,4-tetrahydroisoquinolinyl, 1-oxo-1,2-dihydroisoquinolinyl,4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl,where the heterocyclyl can be bound via either ring of the fused system.As used herein, a bicyclic heterocyclyl group is a heterocyclyl groupattached at two points to another cyclic group, wherein the other cyclicgroup may itself be a heterocyclic group, or a carbocyclic group.

As used herein, the term “nitrogen or sulfur containing heterocyclyl”means a heterocyclyl moiety that contains at least one nitrogen atom orat least one sulfur atom, or both a nitrogen atom and a sulfur atomwithin the ring structure. It is to be understood that otherheteroatoms, including oxygen, may be present in addition to thenitrogen, sulfur, or combinations thereof. Examples of nitrogen orsulfur containing heterocyclyls include morpholinyl, thiomorpholinyl,thiazolyl, isothiazolyl, oxazolidinone 1,2 dithiolyl, piperidinyl,piperazinyl, and the like.

“Hydroxy” or “hydroxyl” refers to the group —OH. “Hydroxyalkyl” refersto an unbranched or branched alkyl group as defined above, wherein oneor more hydrogen atoms are replaced by a hydroxyl.

“Nitro” refers to the group —NO₂.

“Sulfonyl” refers to the group —S(O)₂R, where R is a substituent, or adefined group.

“Alkylsulfonyl” refers to the group —S(O)₂R, where R is a substituent,or a defined group.

“Alkylsulfinyl” refers to the group —S(O)R, where R is a substituent, ora defined group.

“Thiocyanate”—SCN.

“Thiol” refers to the group —SR, where R is a substituent, or a definedgroup.

“Thioxo” or “thione” refer to the group (═S) or (S).

Certain commonly used alternative chemical names may be used. Forexample, a divalent group such as a divalent “alkyl” group, a divalent“aryl” group, etc., may also be referred to as an “alkylene” group or an“alkylenyl” group, an “arylene” group or an “arylenyl” group,respectively. Also, unless indicated explicitly otherwise, wherecombinations of groups are referred to herein as one moiety, e.g.,arylalkyl, the last mentioned group contains the atom by which themoiety is attached to the rest of the molecule.

The terms “optional” or “optionally” means that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where said event or circumstance occursand instances in which it does not. Also, the term “optionallysubstituted” refers to any one or more hydrogen atoms on the designatedatom or group may or may not be replaced by a moiety other thanhydrogen. “Optionally substituted” may be zero to the maximum number ofpossible substitutions, and each occurrence is independent. When theterm “substituted” is used, then that substitution is required to bemade at a substitutable hydrogen atom of the indicated substituent. Anoptional substitution may be the same or different from a (required)substitution.

When a moiety is “optionally substituted,” and reference is made to ageneral term, such as any “alkyl,” “alkenyl,” “alkynyl,” “haloalkyl,”“cycloalkyl,” “aryl” or “heteroaryl,” then the general term can refer toany antecedent specifically recited term, such as (C₁₋₃ alkyl), (C₄₋₆alkyl), —O(C₁₋₄ alkyl), (C₃₋₁₀ cycloalkyl), O—(C₃₋₁₀ cycloalkyl) and thelike. For example, “any aryl” includes both “aryl” and “—O(aryl) as wellas examples of aryl, such as phenyl or naphthyl and the like. Also, theterm “any heterocyclyl” includes both the terms “heterocyclyl” andO-(heterocyclyl),” as well as examples of heterocyclyls, such asoxetanyl, tetrahydropyranyl, morpholino, piperidinyl and the like. Inthe same manner, the term “any heteroaryl” includes the terms“heteroaryl” and “O-(heteroryl),” as well as specific heteroaryls, suchas pyridine and the like.

Some of the compounds exist as tautomers. Tautomers are in equilibriumwith one another. For example, amide containing compounds may exist inequilibrium with imidic acid tautomers. Regardless of which tautomer isshown, and regardless of the nature of the equilibrium among tautomers,the compounds are understood by one of ordinary skill in the art tocomprise both amide and imidic acid tautomers. Thus, the amidecontaining compounds are understood to include their imidic acidtautomers. Likewise, the imidic acid containing compounds are understoodto include their amide tautomers.

Any formula or structure given herein, is also intended to representunlabeled forms as well as isotopically labeled forms of the compounds.Isotopically labeled compounds have structures depicted by the formulasgiven herein except that one or more atoms are replaced by an atomhaving a selected atomic mass or mass number. Examples of isotopes thatcan be incorporated into compounds of the disclosure include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine,such as, but not limited to ²H (deuterium, D), ³H (tritium), ¹¹C, ¹³C,¹⁴C, ¹⁵N, ¹⁸F, ³¹P, ³²P, ³⁵S, ³⁶Cl and ¹²⁵I. Various isotopicallylabeled compounds of the present disclosure, for example those intowhich radioactive isotopes such as ³H, ¹³C and ¹⁴C are incorporated.Such isotopically labelled compounds may be useful in metabolic studies,reaction kinetic studies, detection or imaging techniques, such aspositron emission tomography (PET) or single-photon emission computedtomography (SPECT) including drug or substrate tissue distributionassays or in radioactive treatment of patients.

The disclosure also includes “deuterated analogues” of compounds ofFormula (I) in which from 1 to n hydrogens attached to a carbon atomis/are replaced by deuterium, in which n is the number of hydrogens inthe molecule. Such compounds exhibit increased resistance to metabolismand are thus useful for increasing the half-life of any compound ofFormula (I) when administered to a mammal, particularly a human. See,for example, Foster, “Deuterium Isotope Effects in Studies of DrugMetabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compoundsare synthesized by means well known in the art, for example by employingstarting materials in which one or more hydrogens have been replaced bydeuterium.

Deuterium labelled or substituted therapeutic compounds of thedisclosure may have improved DMPK (drug metabolism and pharmacokinetics)properties, relating to distribution, metabolism and excretion (ADME).Substitution with heavier isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life, reduced dosage requirements and/oran improvement in therapeutic index. An ¹⁸F labeled compound may beuseful for PET or SPECT studies. Isotopically labeled compounds of thisdisclosure and prodrugs thereof can generally be prepared by carryingout the procedures disclosed in the schemes or in the examples andpreparations described below by substituting a readily availableisotopically labeled reagent for a non-isotopically labeled reagent. Itis understood that deuterium in this context is regarded as asubstituent in the compound of Formula I.

The concentration of such a heavier isotope, specifically deuterium, maybe defined by an isotopic enrichment factor. In the compounds of thisdisclosure any atom not specifically designated as a particular isotopeis meant to represent any stable isotope of that atom. Unless otherwisestated, when a position is designated specifically as “H” or “hydrogen”,the position is understood to have hydrogen at its natural abundanceisotopic composition. Accordingly, in the compounds of this disclosureany atom specifically designated as a deuterium (D) is meant torepresent deuterium.

In many cases, the compounds of this disclosure are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto.

Provided are also pharmaceutically acceptable salts, hydrates, solvates,tautomeric forms, polymorphs, and prodrugs of the compounds describedherein. “Pharmaceutically acceptable” or “physiologically acceptable”refer to compounds, salts, compositions, dosage forms and othermaterials which are useful in preparing a pharmaceutical compositionthat is suitable for veterinary or human pharmaceutical use.

The term “pharmaceutically acceptable salt” of a given compound refersto salts that retain the biological effectiveness and properties of thegiven compound, and which are not biologically or otherwise undesirable.“Pharmaceutically acceptable salts” or “physiologically acceptablesalts” include, for example, salts with inorganic acids and salts withan organic acid. In addition, if the compounds described herein areobtained as an acid addition salt, the free base can be obtained bybasifying a solution of the acid salt. Conversely, if the product is afree base, an addition salt, particularly a pharmaceutically acceptableaddition salt, may be produced by dissolving the free base in a suitableorganic solvent and treating the solution with an acid, in accordancewith conventional procedures for preparing acid addition salts from basecompounds. Those skilled in the art will recognize various syntheticmethodologies that may be used to prepare nontoxic pharmaceuticallyacceptable addition salts. Pharmaceutically acceptable acid additionsalts may be prepared from inorganic and organic acids. Salts derivedfrom inorganic acids include hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derivedfrom organic acids include acetic acid, propionic acid, glycolic acid,pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid,maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluene-sulfonic acid, salicylic acid, and the like. Likewise,pharmaceutically acceptable base addition salts can be prepared frominorganic and organic bases. Salts derived from inorganic bases include,by way of example only, sodium, potassium, lithium, ammonium, calciumand magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary and tertiary amines, such asalkyl amines (i.e., NH₂(alkyl)), dialkyl amines (i.e., HN(alkyl)₂),trialkyl amines (i.e., N(alkyl)₃), substituted alkyl amines (i.e.,NH₂(substituted alkyl)), di(substituted alkyl) amines (i.e.,HN(substituted alkyl)₂), tri(substituted alkyl) amines (i.e.,N(substituted alkyl)₃), alkenyl amines (i.e., NH₂(alkenyl)), dialkenylamines (i.e., HN(alkenyl)₂), trialkenyl amines (i.e., N(alkenyl)₃),substituted alkenyl amines (i.e., NH₂(substituted alkenyl)),di(substituted alkenyl) amines (i.e., HN(substituted alkenyl)₂),tri(substituted alkenyl) amines (i.e., N(substituted alkenyl)₃, mono-,di- or tri-cycloalkyl amines (i.e., NH₂(cycloalkyl), HN(cycloalkyl)₂,N(cycloalkyl)₃), mono-, di- or tri-arylamines (i.e., NH₂(aryl),HN(aryl)₂, N(aryl)₃), or mixed amines, etc. Specific examples ofsuitable amines include, by way of example only, isopropylamine,trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine,morpholine, N-ethylpiperidine, and the like.

The term “substituted” means that any one or more hydrogen atoms on thedesignated atom or group is replaced with one or more substituents otherthan hydrogen, provided that the designated atom's normal valence is notexceeded. The one or more substituents include, but are not limited to,alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl,azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo,haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy,hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid,alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof.Polymers or similar indefinite structures arrived at by definingsubstituents with further substituents appended ad infinitum (e.g., asubstituted aryl having a substituted alkyl which is itself substitutedwith a substituted aryl group, which is further substituted by asubstituted heteroalkyl group, etc.) are not intended for inclusionherein. Unless otherwise noted, the maximum number of serialsubstitutions in compounds described herein is three. For example,serial substitutions of substituted aryl groups with two othersubstituted aryl groups are limited to ((substituted aryl)substitutedaryl) substituted aryl. Similarly, the above definitions are notintended to include impermissible substitution patterns (e.g., methylsubstituted with 5 fluorines or heteroaryl groups having two adjacentoxygen ring atoms). Such impermissible substitution patterns are wellknown to the skilled artisan. When used to modify a chemical group, theterm “substituted” may describe other chemical groups defined herein.Unless specified otherwise, where a group is described as optionallysubstituted, any substituents of the group are themselves unsubstituted.For example, in some embodiments, the term “substituted alkyl” refers toan alkyl group having one or more substituents including hydroxyl, halo,alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In otherembodiments, the one or more substituents may be further substitutedwith halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl,aryl, or heteroaryl, each of which is substituted. In other embodiments,the substituents may be further substituted with halo, alkyl, haloalkyl,alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each ofwhich is unsubstituted One skilled in the art will recognize thatsubstituents and other moieties of the compounds of the generic formulaherein should be selected in order to provide a compound which issufficiently stable to provide a pharmaceutically useful compound whichcan be formulated into an acceptably stable pharmaceutical composition.Compounds which have such stability are contemplated as falling withinthe scope of the present invention. It should be understood by oneskilled in the art that any combination of the definitions andsubstituents described above should not result in an inoperable speciesor compound.

As used herein, “pharmaceutically acceptable carrier” or“pharmaceutically acceptable excipient” includes any and all solvents,dispersion media, coatings, antibacterial and antifungal agents,isotonic and absorption delaying agents and the like. The use of suchmedia and agents for pharmaceutically active substances is well known inthe art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions.

A “solvate” is formed by the interaction of a solvent and a compound.Solvates of salts of the compounds described herein are also provided.Hydrates of the compounds described herein are also provided.

Combinations

Patients being treated by administration of the IRAK4 inhibitors of thedisclosure often exhibit diseases or conditions that benefit fromtreatment with other therapeutic agents. These diseases or conditionscan be of an inflammatory nature or can be related to cancer, metabolicdisorders, gastrointestinal disorders and the like. Thus, one aspect ofthe disclosure is a method of treating an inflammation related diseaseor condition, or a metabolic disorder, gastrointestinal disorder, orcancer and the like comprising administering a compound of the incombination with one or more compounds useful for the treatment of suchdiseases to a subject, particularly a human subject, in need thereof.

In some embodiments, a compound of the present disclosure isco-formulated with the additional one or more active ingredients. Insome embodiments, the other active ingredient is administered atapproximately the same time, in a separate dosage form. In someembodiments, the other active ingredient is administered sequentially,and may be administered at different times in relation to a compound ofthe present disclosure.

Combinations for Inflammatory Diseases and Conditions

For example, a compound of the present disclosure may be combined withone or more 5-Lipoxygenase inhibitors, Acetylcholinesterase inhibitors,Acetyl-CoA carboxylase (ACC) inhibitors, ACTH receptor agonists, Activinreceptor antagonists, Acyltransferase inhibitors, Adrenocorticotrophichormone ligands, AKT1 gene inhibitors, Alkaline phosphatase modulators,Alkaline phosphatase stimulators, Androgen receptor agonists,Apolipoprotein C3 antagonists, ASK1 kinase inhibitors, Bactericidalpermeability protein stimulators, Beta adrenoceptor antagonists,Beta-glucuronidase inhibitors, B-lymphocyte antigen CD20 inhibitors,Bradykinin receptor modulators, BTK kinase inhibitors, Calcineurininhibitors, Calcium channel inhibitors, Cannabinoid CB1 receptormodulators, Cannabinoid CB2 receptor modulators, Cannabinoid receptorantagonists, Cannabinoid receptor modulators, Caspase inhibitors,Cathepsin S inhibitors, CCN protein stimulators, CCR3 chemokineantagonists, CCR5 chemokine antagonists, CCR9 chemokine antagonists, CD3modulators, CD40 ligand inhibitors, CD40 ligand receptor antagonists,CD49b antagonists, CD49d antagonists, CD89 agonists, Cell adhesionmolecule inhibitors, Chemokine CXC ligand inhibitors, CHST15 geneinhibitors, Collagen modulators, CSF-1 agonists, CSF-1 antagonists,CXC10 chemokine ligand inhibitors, CXCR2 chemokine antagonists, CyclicGMP phosphodiesterase inhibitors, Cyclooxygenase 2 inhibitors,Cyclooxygenase inhibitors, Cyclooxygenase stimulators, Cytochrome P4503A4 inhibitors, Cytotoxic T-lymphocyte protein-4 stimulators,Dihydroceramide delta 4 desaturase inhibitors, Dihydroorotatedehydrogenase inhibitors, DNA polymerase inhibitors, DPP-4 inhibitors,EGFR family tyrosine kinase receptor modulators, Eosinophil peroxidaseinhibitors, Eotaxin ligand inhibitors, EP4 prostanoid receptor agonists,Epidermal growth factor agonists, Epidermal growth factor ligands,Estrogen receptor beta agonists, Factor XIII agonists, FGF-10 ligands,FGF2 receptor agonists, Fractalkine ligand inhibitors, Free fatty acidreceptor 2 antagonists, FXR agonists, GATA 3 transcription factorinhibitors, Glucagon-like peptide 1 agonists, Glucagon-like peptide 2agonists, Glucocorticoid agonists, GM-CSF receptor agonists, G-proteincoupled receptor 84 antagonists, Guanylate cyclase receptor agonists,Histamine H2 receptor antagonists, Histone acetyltransferase inhibitors,Histone deacetylase inhibitors, HLA class II antigen modulators,Hydrolase inhibitors, HSD17β13 inhibitors, ICAM1 gene inhibitors, ICAM-1inhibitors, IL1 gene inhibitors, IL-10 agonists, IL10 gene stimulators,IL-11 agonists, IL-12 antagonists, IL12 gene inhibitors, IL-13antagonists, IL-17 antagonists, IL-2 antagonists, IL-2 receptor alphasubunit inhibitors, IL-21 antagonists, IL-23 antagonists, IL-6antagonists, IL6 gene inhibitors, IL-6 receptor modulators, IL-7antagonists, IL-8 antagonists, Immunoglobulin G1 agonists,Immunoglobulin G2 modulators, Inosine monophosphate dehydrogenaseinhibitors, Insulin sensitizers, Integrin alpha-4/beta-1 antagonists,Integrin alpha-4/beta-7 antagonists, Integrin alpha-E antagonists,Integrin antagonists, Integrin beta-7 antagonists, Interferon betaligands, Interleukin 17E ligand inhibitors, Interleukin ligandinhibitors, Interleukin receptor 17A antagonists, Interleukin receptor17B antagonists, Interleukin-1 beta ligands, Interleukin-1 beta ligandmodulators, Interleukin-6 ligand inhibitors, JAK tyrosine kinaseinhibitors, Jak1 tyrosine kinase inhibitors, JAK2 gene inhibitors, Jak3tyrosine kinase inhibitors, Jun N terminal kinase inhibitors, LanC likeprotein 2 modulators, Leukotriene BLT receptor antagonists, Lipoxygenasemodulators, L-Selectin antagonists, MAdCAM inhibitors, Matrixmetalloprotease inhibitors, Matrix metalloprotease modulators,Melanocortin agonists, Membrane copper amine oxidase inhibitors,Metalloprotease-2 inhibitors, Metalloprotease-9 inhibitors, MIP 3 alphaligand inhibitors, Mitochondrial 10 kDa heat shock protein stimulators,Monocyte differentiation antigen CD14 inhibitors, mTOR inhibitors, Mucinstimulators, NAD-dependent deacetylase sirtuin-1 stimulators,Natriuretic peptide receptor C agonists, Neuregulin-4 ligands, Nicotinicacetylcholine receptor agonists, Nicotinic ACh receptor alpha 4 subunitmodulators, Nicotinic ACh receptor alpha 7 subunit stimulators,Nicotinic ACh receptor beta 2 subunit modulators, NK1 receptorantagonists, NKG2 D activating NK receptor antagonists, Nuclear factorkappa B inhibitors, Opioid growth factor receptor agonists, Opioidreceptor antagonists, Opioid receptor delta antagonists, Oxidoreductaseinhibitors, P2X7 purinoceptor agonists, p38 MAP kinase inhibitors, PARPinhibitors, PDE 4 inhibitors, PDGF receptor agonists, Phagocytosisstimulating peptide modulators, Phospho MurNAc pentapeptide transferaseinhibitors, Phospholipase A2 inhibitors, Platelet activating factorreceptor antagonists, Potassium channel inhibitors, PPAR alpha agonists,PPAR delta agonists, PPAR gamma agonists, Protein CYR61 stimulators,Protein fimH inhibitors, Protein kinase C alpha inhibitors, Proteinkinase C beta inhibitors, Protein kinase C delta inhibitors, Proteinkinase C epsilon inhibitors, Protein kinase C eta inhibitors, Proteinkinase C theta inhibitors, Protein kinase G inhibitors, Protein kinaseinhibitors, P-selectin glycoprotein ligand-1 inhibitors, PurH purinebiosynthesis protein inhibitors, Retinoic acid receptor alpha agonists,Retinoic acid receptor beta agonists, Retinoid receptor agonists, RNApolymerase inhibitors, SMAD-7 inhibitors, Sodium channel inhibitors,Somatostatin receptor agonists, Sphingosine 1 phosphate phosphatase 1stimulators, Sphingosine 1 phosphate phosphatase modulators, Sphingosinekinase 1 inhibitors, Sphingosine kinase 2 inhibitors,Sphingosine-1-phosphate receptor-1 agonists, Sphingosine-1-phosphatereceptor-1 antagonists, Sphingosine-1-phosphate receptor-1 modulators,Sphingosine-1-phosphate receptor-5 modulators, STAT3 gene inhibitors,STAT-3 inhibitors, STAT-4 inhibitors, Stem cell antigen-1 inhibitors,Superoxide dismutase modulators, Superoxide dismutase stimulators, SYKkinase inhibitors, T cell surface glycoprotein CD28 inhibitors, TGF beta1 ligand inhibitors, Thymulin agonists, THR-β agonists, TLR-2antagonists, TLR-4 antagonists, TLR-9 agonists, TNF alpha ligandinhibitors, TNF alpha ligand modulators, TNF antagonists, TPL2 kinaseinhibitors, Trefoil factor modulators, Tryptase inhibitors, Tryptophan5-hydroxylase inhibitors, Tumor necrosis factor 14 ligand modulators,TYK2 kinase inhibitors, Type I TNF receptor antagonists, Type II TNFreceptor modulators, Unspecified growth factor receptor modulators,Vanilloid VR1 agonists, Vitamin D3 receptor agonists, Zonulininhibitors, abatacept; acemannan; adalimumab; DCCT-10; apremilast;AST-120; balsalazide; balsalazide sodium; basiliximab; beclomethasonedipropionate; budesonide; D-9421; budesonide MMX; catridecacog;certolizumab pegol; Clostridium butyricum; etanercept; fingolimod;glatiramer acetate; golimumab; infliximab; infliximab biosimilar;infliximab follow-on biologic; interferon beta-1a; lenalidomide;mesalazine; GED-0001; AJG-501; metenkefalin acetate with tridecactideacetat, mycophenolate mofetil; naltrexone; natalizumab; nitazoxanide;olsalazine; oprelvekin; propionyl-L-camitine; recombinant interferonbeta-1a; remestemcel-L; rifaximin; rituximab; ropivacaine;rosiglitazone; sargramostim; secukinumab; SPD-480; tacrolimus;tamibarotene; teduglutide; thalidomide; tocilizumab; RO-4877533;tofacitinib; CP-690550; Trichuris suis ova; ASP-1002; ustekinumab;valganciclovir; vedolizumab; zileuton; anti-CD3 imaging agent (antibodyfragment, cancer/autoimmune disease), ImaginAb; AVX-470; ciclosporin;CXCR1/2 ligands mAb (immunology), Eli Lilly; FFP-102; GSK-3050002;INN-108; IR-777; SGM-1019; peg-ilodecakin; PF-06480605; PF-06651600;SER-287; Syn-1002; Thetanix; tolerogenic dendritic cell therapyTOP-1288; VBY-036; VBY-129; 946414-98-8; BMS-936557; 99mTc-annexinV-128; ABC-294640; abrilumab; Alequel; AMG-139; amiselimod; APD-334;ASP-3291; beclomethasone dipropionate; bertilimumab; ciclosporin;clazakizumab; DLX-105; dolcanatide; E-6011; ETX-201; FFP-104;filgotinib; foralumab; GED-0507-34-Levo; givinostat; GLPG-0974;GLPG-1205; iberogast N (ulcerative colitis), Bayer; BAY98-7410; INV-103;JNJ-40346527; K(D)PT; KAG-308; KHK-4083; KRP-203; larazotide acetate;CB-01-05-MMX; LY-3074828; mesalamine with N-acetylcysteine; midismase;molgramostim follow on biologic with fosfomycin with carbapenem,Reponex; multipotent adult progenitor cell therapy (ischemia/cerebralpalsy), Athersys/Healios; NN-8828; olokizumab; OvaSave; P-28-GST;PDA-002; PF-4236921; PF-547659; prednisolone; PUR-0110; QBECO; RBX-2660;repurposed naltrexone; JKB-122; SB-012; sotrastaurin; STNM-01; TAK-114;tetomilast; Debio-0512; TRK-170; TRX-318; vatelizumab; VB-201; ZP-1848;zucapsaicin; ABT-494; alicaforsen; Ampion; BI-655066; briakinumab;cannabidiol; carotegast methyl; cobitolimod; dexamethasone sodiumphosphate; elafibranor; etrolizumab; GS-5745; HMPL-004; LP-02;mesalazine; metronidazole mongersen; ocrelizumab; ozanimod; peficitinib;RHB-104; rifaximin; tildrakizumab; tralokinumab; brodalumab; laquinimod;plecanatide; telotristat etiprate; infliximab biosimilar, SamsungBioepis; AZD-058; and rifabutin with clarithromycin and further withclofazimine.

Also, the following non-exhaustive list of classes of compounds andcompounds may be combined with a compound of the present disclosure:5-Lipoxygenase inhibitors, such as zileuton, etalocibm FPL-64170,E-3040, and BU-4601A; Acetylcholinesterase inhibitors, such as BL-7040;ACTH receptor agonists, such as metenkefalin acetate with tridecactideacetate, and FAR-404; Activin receptor antagonists such as follistatin;Acyltransferase inhibitors such as AZD-0585; Adrenocorticotrophichormone ligands, such as metenkefalin acetate with tridecactide acetate,and FAR-404; AKT1 gene inhibitors, such as vidofludimus; Alkalinephosphatase modulators such as recombinant human alkaline phosphatase(oral, ulcerative colitis), AM-Pharma; Alkaline phosphatase stimulatorssuch as bovine alkaline phosphatase; Androgen receptor agonists, such asPB-005; Apolipoprotein C3 antagonists, such as AZD-0585; Bactericidalpermeability protein stimulators, such as opebacan; Beta adrenoceptorantagonists, such as NM-001; Beta-glucuronidase inhibitors, such asKD-018; B-lymphocyte antigen CD20 inhibitors, such as ocrelizumab,rituximab; Bradykinin receptor modulators, such as givinostat;Calcineurin inhibitors, such as tacrolimus, ciclosporin; Calcium channelinhibitors, such as clotrimazole; Cannabinoid CB1 receptor modulators,such as GWP42003-P, cannabidiol; Cannabinoid CB2 receptor modulators,such as GWP42003-P, cannabidiol; Cannabinoid receptor antagonists, suchas fingolimod; Cannabinoid receptor modulators, such as GWP42003-P,cannabidiol; Cathepsin S inhibitors, such as VBY-129, VBY-036; CCNprotein stimulators, such as CSA-13; CCR3 chemokine antagonists, such asbertilimumab; CCR5 chemokine antagonists, such as HGS-1025; CCR9chemokine antagonists, such as MLN-3126, vercimon, CCX-025; CD3modulators, such as visilizumab; CD40 ligand inhibitors, such asFFP-104; CD40 ligand receptor antagonists, such as FFP-104, FFP-102,toralizumab; CD49b antagonists, such as vatelizumab; CD49d antagonists,such as ELND-004; CD89 agonists, such as HF-1020; Cell adhesion moleculeinhibitors, such as natalizumab, alicaforsen (intravenous), ASP-2002,ISIS-2302; Chemokine CXC ligand inhibitors, such as CXCR1/2 ligands mAb(immunology), Eli Lilly; CHST15 gene inhibitors, such as STNM-01;Collagen modulators, such as adipose-derived stem cell therapy (CelutionSystem), Cytori, DCCT-10; CSF-1 agonists, such as sargramostim,molgramostim follow on biologic with fosfomycin with carbapenem(intraintestinal, Crohn's disease), Reponex; CSF-1 antagonists, such asJNJ-40346527; CXC10 chemokine ligand inhibitors, such as 946414-98-8,BMS-936557; CXCR2 chemokine antagonists, such as elubrixin; Cyclic GMPphosphodiesterase inhibitors, such as CEL-031; Cyclooxygenase 2inhibitors, such as P-54; Cyclooxygenase inhibitors, such as mesalazine,4-aminosalicylate sodium, AJG-501, AGI-022; Cyclooxygenase stimulators,such as nicotine polacrilex; Cytochrome P450 3A4 inhibitors, such asKD-018; Cytotoxic T-lymphocyte protein-4 stimulators, such as abatacept;Dihydroceramide delta 4 desaturase inhibitors, such as ABC-294640;Dihydroorotate dehydrogenase inhibitors, such as vidofludimus; DNApolymerase inhibitors, such as valganciclovir; EGFR family tyrosinekinase receptor modulators, such as neuregulin 4 (Crohn'sdisease/ulcerative colitis/necrotizing enterocolitis), AvexegenTherapeutics/Children's Hospital of Los Angeles; Eosinophil peroxidaseinhibitors, such as AWEPOPD-01, AWEPO-003; Eotaxin ligand inhibitors,such as bertilimumab; EP4 prostanoid receptor agonists, such as KAG-308;Epidermal growth factor agonists, such as heparin-EGF-like factor, SciosNova; Epidermal growth factor ligands, such as Hebervis; Estrogenreceptor beta agonists, such as prinaberel; Factor XIII agonists, suchas catridecacog; FGF-10 ligands, such as repifermin; FGF2 receptoragonists, such as F2A; Fractalkine ligand inhibitors, such as E-6011;Free fatty acid receptor 2 antagonists, such as GLPG-0974; GATA 3transcription factor inhibitors, such as SB-012; Glucagon-like peptide 2agonists, such as teduglutide, ZP-1848, NB-1002; Glucocorticoidagonists, such as budesonide, beclomethasone dipropionate, dexamethasonesodium phosphate, AJG-511, DOR-201, D-9421-C; GM-CSF receptor agonists,such as sargramostim, molgramostim follow on biologic with fosfomycinwith carbapenem (intraintestinal, Crohn's disease), Reponex; G-proteincoupled receptor 84 antagonists, such as GLPG-1205; Guanylate cyclasereceptor agonists, such as dolcanatide, SP-333; Histamine H2 receptorantagonists, such as bismuth, Medeva; Histone acetyltransferaseinhibitors, such as TIP60 inhibitors (ulcerative colitis/inflammatorybowel disease/autoimmune diseases), University of Pennsylvania; Histonedeacetylase inhibitors, such as givinostat; HLA class II antigenmodulators, such as HLA class II protein modulators (Crohns disease),Nextera AS; Hydrolase inhibitors, such as SC-56938; ICAM1 geneinhibitors, such as alicaforsen; ICAM-1 inhibitors, such as alicaforsen(intravenous), ISIS-2302; IL1 gene inhibitors, such as PLR-14; IL-10agonists, such as peg-ilodecakin, AM-0010; IL10 gene stimulators, suchas gene therapy (IL-10), Imperial College; IL-11 agonists, such asoprelvekin, YM-294; IL-12 antagonists, such as ustekinumab, briakinumab,apilimod; IL12 gene inhibitors, such as RDP-58; IL-13 antagonists, suchas tralokinumab, anrukinzumab; IL-17 antagonists, such as secukinumab,vidofludimus; IL-2 antagonists, such as daclizumab; IL-2 receptor alphasubunit inhibitors, such as basiliximab, daclizumab, BSX-003,Ro-34-7375; IL-21 antagonists, such as NN-8828, ATR-107; IL-23antagonists, such as tildrakizumab, ustekinumab, BI-655066, AMG-139,briakinumab, LY-3074828, apilimod; IL-6 antagonists, such astocilizumab, clazakizumab, olokizumab, HMPL-004, AMG-220, FM-101; IL6gene inhibitors, such as YSIL6-T-PS; IL-6 receptor modulators, such astocilizumab; IL-7 antagonists, such as interleukin-7 receptor modulators(ulcerative colitis/T-cell acute lymphoblastic leukaemia), Effimune;IL-8 antagonists, such as elubrixin, clotrimazole; Immunoglobulin G1agonists, such as HF-1020; Immunoglobulin G2 modulators, such asPF-547659; Inosine monophosphate dehydrogenase inhibitors, such asmycophenolate mofetil; Insulin sensitizers, such as elafibranor,rosiglitazone, HE-3286, EGS-21; Integrin alpha-4/beta-1 antagonists,such as natalizumab, TRK-170, firategrast; Integrin alpha-4/beta-7antagonists, such as etrolizumab, vedolizumab, abrilumab, carotegastmethyl, TRK-170, firategrast; Integrin alpha-E antagonists, such asetrolizumab; Integrin antagonists, such as vatelizumab, ASP-2002;Integrin beta-7 antagonists, such as etrolizumab; Interferon betaligands, such as interferon beta-1a, recombinant interferon beta-1a,Serono; Interleukin 17E ligand inhibitors, such as anti-IL-17BRhumanized antibody (lung fibrosis/asthma/ulcerative colitis), MedicalResearch Council Technology; Interleukin ligand inhibitors, such asHE-3286; Interleukin receptor 17A antagonists, such as brodalumab;Interleukin receptor 17B antagonists, such as anti-IL-17BR humanizedantibody (lung fibrosis/asthma/ulcerative colitis), Medical ResearchCouncil Technology; Interleukin-1 beta ligands, such as K(D)PT,PUR-0110, HMPL-004; Interleukin-1 beta ligand modulators, such asPUR-0110, HMPL-004; Interleukin-6 ligand inhibitors, such as PF-4236921;JAK tyrosine kinase inhibitors, such as tofacitinib, peficitinib; Jak1tyrosine kinase inhibitors, such as ABT-494, tofacitinib, filgotinib,peficitinib, GLPG-0555, solcitinib; JAK2 gene inhibitors, such asvidofludimus; Jak3 tyrosine kinase inhibitors, such as tofacitinib,peficitinib; Jun N terminal kinase inhibitors, such as semapimod; LanClike protein 2 modulators, such as BT-11; Leukotriene BLT receptorantagonists, such as ONO-4057, etalocib, SC-53228, SC-52798;Lipoxygenase modulators, such as mesalazine; L-Selectin antagonists,such as BNP-001; MAdCAM inhibitors, such as vedolizumab, PF-547659;Matrix metalloprotease inhibitors, such as D-5410; Matrixmetalloprotease modulators, such as D-5410; Melanocortin agonists, suchas ASP-3291; Membrane copper amine oxidase inhibitors, such asvepalimomab; Metalloprotease-2 inhibitors, such as KD-018, RWJ-68354;Metalloprotease-9 inhibitors, such as GS-5745; MIP 3 alpha ligandinhibitors, such as GSK-3050002; Mitochondrial 10 kDa heat shock proteinstimulators, such as INV-103; Monocyte differentiation antigen CD14inhibitors, such as CD14 anti-inflammatory, Cornell; mTOR inhibitors,such as P-2281; Mucin stimulators, such as rebamipide; NAD-dependentdeacetylase sirtuin-1 stimulators, such as SRT-2104; Natriuretic peptidereceptor C agonists, such as plecanatide; Neuregulin-4 ligands, such asneuregulin 4 (Crohn's disease/ulcerative colitis/necrotizingenterocolitis), Avexegen Therapeutics/Children's Hospital of LosAngeles; Nicotinic acetylcholine receptor agonists, such as TC-2403,nicotine polacrilex, nicotine; Nicotinic ACh receptor alpha 4 subunitmodulators, such as TC-2403; Nicotinic ACh receptor alpha 7 subunitstimulators, such as GTS-21; Nicotinic ACh receptor beta 2 subunitmodulators, such as TC-2403; NK1 receptor antagonists, such as KD-018,nolpitantium besilate; NKG2 D activating NK receptor antagonists, suchas NNC-0142-002; Nuclear factor kappa B inhibitors, such as KD-018,cobitolimod, CSA-13, HE-3286, HMPL-004, Avrina, mesalamine withN-acetylcysteine, P-54; Opioid growth factor receptor agonists, such asmetenkefalin acetate with tridecactide acetate, FAR-404; Opioid receptorantagonists, such as naltrexone, IRT-103; Opioid receptor deltaantagonists, such as KD-018; Oxidoreductase inhibitors, such asolsalazine; P2X7 purinoceptor agonists, such as givinostat; p38 MAPkinase inhibitors, such as RDP-58, doramapimod, semapimod, RWJ-68354;PARP inhibitors, such as EB-47, INO-1003; PDE 4 inhibitors, such asapremilast, tetomilast, CC-1088; PDGF receptor agonists, such asoprelvekin, YM-294; Phagocytosis stimulating peptide modulators, such as99mTc-RP-128; Phospho MurNAc pentapeptide transferase inhibitors, suchas SQ-641; Phospholipase A2 inhibitors, such as varespladib methyl;Platelet activating factor receptor antagonists, such as dersalazinesodium; Potassium channel inhibitors, such as clotrimazole; PPAR alphaagonists, such as elafibranor (GFT-1007); PPAR delta agonists, such aselafibranor (GFT-1007); PPAR gamma agonists, such as rosiglitazone,GED-0507-34-Levo, etalocib; Protein CYR61 stimulators, such as CSA-13;Protein fimH inhibitors, such as EB-8018; Protein kinase C alphainhibitors, such as sotrastaurin (AEB-071); Protein kinase C betainhibitors, such as sotrastaurin (AEB-071); Protein kinase C deltainhibitors, such as sotrastaurin (AEB-071); Protein kinase C epsiloninhibitors, such as sotrastaurin (AEB-071); Protein kinase C etainhibitors, such as sotrastaurin (AEB-071); Protein kinase C thetainhibitors, such as sotrastaurin (AEB-071); Protein kinase G inhibitors,such as CEL-031; Protein kinase inhibitors, such as TOP-1288; P-selectinglycoprotein ligand-1 inhibitors, such as SEL-K2; PurH purinebiosynthesis protein inhibitors, such as mycophenolate mofetil; Retinoicacid receptor alpha agonists, such as tamibarotene; Retinoic acidreceptor beta agonists, such as tamibarotene; Retinoid receptoragonists, such as tamibarotene; RNA polymerase inhibitors, such asrifaximin; SMAD-7 inhibitors, such as mongersen (GED-0301); Sodiumchannel inhibitors, such as ropivacaine; Somatostatin receptor agonists,such as vapreotide; Sphingosine 1 phosphate phosphatase 1 stimulators,such as APD-334; Sphingosine 1 phosphate phosphatase modulators, such asS1P modulators (oral, multiple sclerosis/ulcerative colitis/rheumatoidarthritis), Akaal Pharma; Sphingosine kinase 1 inhibitors, such asABC-294640; Sphingosine kinase 2 inhibitors, such as ABC-294640;Sphingosine-1-phosphate receptor-1 agonists, such as ozanimod(RPC-1063), KRP-203; Sphingosine-1-phosphate receptor-1 antagonists,such as amiselimod (MT-1303); Sphingosine-1-phosphate receptor-1modulators, such as fingolimod (FTY-720), ozanimod (RPC-1063),amiselimod (MT-1303); Sphingosine-1-phosphate receptor-5 modulators,such as ozanimod; STAT3 gene inhibitors, such as vidofludimus; STAT-3inhibitors, such as TAK-114; STAT-4 inhibitors, such as STAT-4 antisenseoligonucleotide (Crohns disease/colitis), NIAID; Stem cell antigen-1inhibitors, such as Ampion, DMI-9523; Superoxide dismutase modulators,such as midismase, LT-0011; Superoxide dismutase stimulators, such assuperoxide dismutase; T cell surface glycoprotein CD28 inhibitors, suchas abatacept; TGF beta 1 ligand inhibitors, such as mongersen, GED-0301;Thymulin agonists, such as Syn-1002; TLR-2 antagonists, such as VB-201;TLR-4 antagonists, such as JKB-122, VB-201; TLR-9 agonists, such asBL-7040, cobitolimod; TNF alpha ligand inhibitors, such as adalimumab,certolizumab pegol, infliximab biosimilar, infliximab, golimumab,ISIS-104838, CSA-13, DLX-105, adalimumab biosimilar, dersalazine sodium,Debio-0512, HMPL-004, DLX-105, infliximab follow-on biologic, AZD-9773,CYT-020-TNFQb, DOM-0200; TNF alpha ligand modulators, such as PUR-0110,CDP-571; TNF antagonists, such as etanercept, certolizumab pegol,AVX-470, onercept; Trefoil factor modulators, such as AG-012; Tryptaseinhibitors, such as APC-2059; Tryptophan 5-hydroxylase inhibitors, suchas telotristat etiprate; Tumor necrosis factor 14 ligand modulators,such as SAR-252067; Type I TNF receptor antagonists, such as DOM-0100;Type II TNF receptor modulators, such as etanercept; Unspecified growthfactor receptor modulators, such as AP-005; Vanilloid VR1 agonists, suchas zucapsaicin; Vitamin D3 receptor agonists, such as calcitriol; andZonulin inhibitors, such as larazotide acetate, AT-1001.

Also, the following non-exhaustive list of classes of compounds andcompounds may be combined with a compound of the present disclosure:14-3-3 protein eta inhibitors, 5-Lipoxygenase inhibitors, Abl tyrosinekinase inhibitors, ACTH receptor agonists, Adenosine A3 receptoragonists, Adenosine deaminase inhibitors, ADP ribosyl cyclase-1modulators, ADP ribosylation factor 6 inhibitors, Adrenocorticotrophichormone ligands, Aggrecanase-2 inhibitors, Albumin modulators, APltranscription factor inhibitors, Basigin inhibitors, Bcr proteininhibitors, B-lymphocyte antigen CD19 inhibitors, B-lymphocyte antigenCD20 inhibitors, B-lymphocyte antigen CD20 modulators, B-lymphocytestimulator ligand inhibitors, Bradykinin receptor modulators, BRAF geneinhibitors, Branched amino acid aminotransferase 1 inhibitors,Bromodomain containing protein inhibitors, Btk tyrosine kinaseinhibitors, Cadherin-11 antagonists, Calcineurin inhibitors, Calciumchannel inhibitors, Carbonic anhydrase inhibitors, Cathepsin Kinhibitors, Cathepsin S inhibitors, CCR1 chemokine antagonists, CCR2chemokine antagonists, CCR3 gene modulators, CCR5 chemokine antagonists,CD126 antagonists, CD29 modulators, CD3 modulators, CD39 agonists, CD4agonists, CD4 antagonists, CD40 ligand inhibitors, CD40 ligand receptorantagonists, CD40 ligand receptor modulators, CD52 antagonists, CD73agonists, CD79b modulators, CD80 antagonists, CD86 antagonists, CD95antagonists, Cell adhesion molecule inhibitors, Choline kinaseinhibitors, Clusterin stimulators, Complement C5 factor inhibitors,Complement Factor stimulators, C-reactive protein inhibitors, CSF-1antagonists, CXC10 chemokine ligand inhibitors, CXCR4 chemokineantagonists, Cyclin-dependent kinase inhibitor 1 inhibitors,Cyclin-dependent kinase-2 inhibitors, Cyclin-dependent kinase-4inhibitors, Cyclin-dependent kinase-5 inhibitors, Cyclin-dependentkinase-6 inhibitors, Cyclin-dependent kinase-7 inhibitors,Cyclin-dependent kinase-9 inhibitors, Cyclooxygenase 2 inhibitors,Cyclooxygenase 2 modulators, Cyclooxygenase inhibitors, Cytosolicphospholipase A2 inhibitors, Cytotoxic T-lymphocyte protein-4modulators, Cytotoxic T-lymphocyte protein-4 stimulators, DHFRinhibitors, Diamine acetyltransferase inhibitors, Dihydroorotatedehydrogenase inhibitors, Elongation factor 2 inhibitors, Eotaxin 2ligand inhibitors, EP4 prostanoid receptor antagonists, Erythropoietinreceptor agonists, Fas ligands, FGF-2 ligand inhibitors, FK506 bindingprotein-12 modulators, Folate antagonists, Folate receptor agonists,Folate receptor beta antagonists, Folate receptor modulators,Fractalkine ligand inhibitors, Fyn tyrosine kinase inhibitors, G proteincoupled receptor 15 antagonists, GABA A receptor modulators,Glucocorticoid agonists, Glucocorticoid antagonists, Glucocorticoidinduced leucine zipper stimulators, GM-CSF ligand inhibitors, GM-CSFreceptor antagonists, GM-CSF receptor modulators, Growth regulatedprotein alpha ligand inhibitors, Hwith Kwith ATPase inhibitors,Histamine H4 receptor antagonists, Histone deacetylase inhibitors,Histone deacetylase-6 inhibitors, HIV-1 gp120 protein inhibitors, HLAclass II antigen DQ-2 alpha modulators, HLA class II antigen inhibitors,HLA class II antigen modulators, Hsp 70 family inhibitors, Hypoxiainducible factor-1 inhibitors, IFNB gene stimulators, I-kappa B kinasebeta inhibitors, I-kappa B kinase inhibitors, IL-1 antagonists, IL-10agonists, IL-11 agonists, IL-12 antagonists, IL-15 antagonists, IL-17antagonists, IL-17 receptor modulators, IL-2 agonists, IL-2 antagonists,IL-21 antagonists, IL-23 antagonists, IL-3 antagonists, IL-4 agonists,IL-6 antagonists, IL-6 receptor modulators, Immunoglobulin antagonists,Immunoglobulin G1 agonists, Immunoglobulin G1 antagonists,Immunoglobulin G1 modulators, Immunoglobulin G2 antagonists,Immunoglobulin G2 modulators, Immunoglobulin gamma Fc receptor IImodulators, Immunoglobulin gamma Fc receptor IIB antagonists,Immunoglobulin kappa modulators, Immunoglobulin M antagonists, Induciblenitric oxide synthase inhibitors, Inosine monophosphate dehydrogenaseinhibitors, Insulin sensitizers, Integrin alpha-1/beta-1 antagonists,Integrin alpha-4/beta-1 antagonists, Integrin antagonists, Interferonbeta ligands, Interferon gamma ligands, Interleukin 17A ligandinhibitors, Interleukin 17F ligand inhibitors, Interleukin 23Ainhibitors, Interleukin ligands, Interleukin receptor 17A antagonists,Interleukin-1 beta ligand inhibitors, Interleukin-10 ligands,Interleukin-2 ligands, Interleukin-4 ligands, Interleukin-6 ligandinhibitors, Itk tyrosine kinase inhibitors, JAK tyrosine kinaseinhibitors, Jak1 tyrosine kinase inhibitors, Jak2 tyrosine kinaseinhibitors, JAK3 gene inhibitors, Jak3 tyrosine kinase inhibitors, Jun Nterminal kinase inhibitors, KCNA voltage-gated potassium channel-3modulators, Kelch like ECH associated protein 1 modulators, Kit tyrosinekinase inhibitors, LanC like protein 2 modulators, LITAF geneinhibitors, Lymphocyte function antigen-3 receptor antagonists, Lyntyrosine kinase inhibitors, Macrophage mannose receptor 1 modulators,MAdCAM inhibitors, MAP kinase modulators, MAP3K2 gene inhibitors,MAPKAPK5 inhibitors, Matrix metalloprotease inhibitors, MCL1 geneinhibitors, MEK protein kinase inhibitors, MEK-1 protein kinaseinhibitors, MEK-2 protein kinase inhibitors, Membrane copper amineoxidase inhibitors, Metalloprotease-2 inhibitors, Metalloprotease-9inhibitors, Midkine ligand inhibitors, Mitochondrial 10 kDa heat shockprotein stimulators, mTOR complex 1 inhibitors, mTOR inhibitors, NAD ADPribosyltransferase stimulators, NAMPT gene inhibitors, NF kappa Binhibitor stimulators, NFAT gene inhibitors, NFE2L2 gene stimulators,Nicotinic acetylcholine receptor antagonists, NK cell receptormodulators, NKG2 A B activating NK receptor antagonists, NKG2 Dactivating NK receptor antagonists, Nuclear erythroid 2-related factor 2stimulators, Nuclear factor kappa B inhibitors, Nuclear factor kappa Bmodulators, Nuclear factor kappa B p105 inhibitors, Opioid growth factorreceptor agonists, Opioid receptor delta antagonists, Osteoclastdifferentiation factor antagonists, Osteoclast differentiation factorligand inhibitors, Oxidoreductase inhibitors, P2X7 purinoceptoragonists, p38 MAP kinase alpha inhibitors, p38 MAP kinase inhibitors,PDE 4 inhibitors, PDE 5 inhibitors, PDGF receptor agonists, PDGFreceptor antagonists, PDGF-B ligand inhibitors, PERK gene inhibitors,Phosphoinositide-3 kinase delta inhibitors, Phosphoinositide-3 kinasegamma inhibitors, Phospholipase A2 inhibitors, Platelet activatingfactor receptor antagonists, PPAR gamma agonists, Programmed cell deathprotein 1 modulators, Prostaglandin D synthase stimulators, Proteinarginine deiminase inhibitors, Protein tyrosine kinase inhibitors, PurHpurine biosynthesis protein inhibitors, Rho associated protein kinase 2inhibitors, Seprase inhibitors, Signal transducer CD24 modulators,Signal transduction inhibitors, Sodium glucose transporter-2 inhibitors,Sphingosine 1 phosphate phosphatase modulators, STAT3 gene inhibitors,Superoxide dismutase stimulators, SYK family tyrosine kinase inhibitors,Syk tyrosine kinase inhibitors, Syndecan-1 inhibitors, T cell receptorantagonists, T cell receptor modulators, T cell surface glycoproteinCD28 inhibitors, T cell surface glycoprotein CD28 stimulators, TAK1binding protein modulators, Talin modulators, T-cell differentiationantigen CD6 inhibitors, T-cell surface glycoprotein CD8 inhibitors,Tenascin modulators, TGF beta agonists, Thymulin agonists, TLR-2antagonists, TLR-4 antagonists, TLR-9 antagonists, TNF alpha ligandinhibitors, TNF alpha ligand modulators, TNF antagonists, TNF geneinhibitors, TNF receptor modulators, TNFSF11 gene inhibitors,Transcription factor p65 inhibitors, Transcription factor RelBinhibitors, Transferrin modulators, Tumor necrosis factor 13C receptorantagonists, Tumor necrosis factor 15 ligand inhibitors, Tumor necrosisfactor ligand 13 inhibitors, Tumor necrosis factor ligand inhibitors,Type I IL-1 receptor antagonists, Type I TNF receptor antagonists, TypeII TNF receptor modulators, Unspecified GPCR agonists, VEGF receptorantagonists, VEGF-2 receptor antagonists, VEGF-2 receptor modulators,VEGF-B ligand inhibitors, X-linked inhibitor of apoptosis proteininhibitors, Zap70 tyrosine kinase inhibitors, 99mTc labelled annexinV-128, abatacept, abatacept biosimilar, ABBV-257, ABT-122, ABT-494,acalabrutinib, aceclofenac, actarit, MS-392, adalimumab, adalimumabbiosimilar, adalimumab follow-on biologic, AK-106, ALX-0061,aminopterin, anakinra, anakinra biosimilar, anakinra follow-on biologic,ARG-301, ASLAN-003, ASP-5094, AT-132, AZD-9567, baricitinib, BI-655064,bimekizumab, BiP (rheumatoid arthritis), Kings College London, BLHP-006,blisibimod, BMS-986104, BMS-986142, ABBV-105, BTT-1023, canakinumab,Cartistem, CCX-354, CD24-IgFc, celecoxib, cerdulatinib, certolizumabpegol, CF-101, CFZ-533, CHR-5154, cibinetide, ciclosporin, clazakizumab,CNTO-6785, corticotropin, Mallinckrodt, CR-6086, CreaVax-RA, CWG-92,CWG-940, Cx-611, DE-098, deflazacort, Rheumavax, denosumab, diacerein,diclofenac, E-6011, eicosapentaenoic acid monoglycerides, etanercept,etanercept biosimilar, etanercept follow-on biologic, etodolac,etoricoxib, filgotinib, fosdagrocorat, gerilimzumab, ginsenoside C-K,givinostat, goat polyclonal antibodies, golimumab, GS-5745, GS-9876,GSK-3196165, HM-71224, HMPL-523, hyaluronate sodium, IB-RA (injectable,rheumatoid arthritis), Innobioscience, IB-RA (oral, rheumatoidarthritis), Innobioscience, iguratimod, IMD-2560, imidazole salicylate,infliximab, infliximab biobetter, infliximab biosimilar, INSIX RA,interferon gamma follow-on biologic, interleukin-2 (injectable),interleukin-2 follow-on biologic, INV-103, IR-501, itolizumab,JNJ-40346527, Ka Shu Ning, KD-025, ketoprofen with omeprazole,leflunomide, lenzilumab, LLDT-8, lumiracoxib, LY-3090106, masitinib,mavrilimumab, MBS-2320, MEDI-5117, meloxicam, methotrexate, MGD-010,misoprostol with diclofenac, MM-A01-01, monalizumab, MORAb-022,MPC-300-IV, MRC-375, nabumetone, namilumab, naproxen with esomeprazole,naproxen with esomeprazole strontium, ocaratuzumab, ofatumumab, OHR-118,olokizumab, OM-89, once-daily naproxen (oral controlled release, pain),Alvogen, ONO-4059, Oralgam, ozoralizumab, peficitinib, pelubiprofen,PF-06687234, piperidone hydrochloridum, piroxicam, prednisolone,prednisone, Prosorba, PRT-2607, PRTX-100, PRX-167700, QBSAU, rabeximod,RCT-18, recombinant human CD22 monoclonal antibody (iv infusion), LonnRyonn Pharma/SinoMab Bioscience (Shenzhen), recombinant humaninterleukin-1 receptor antagonist (rheumatoid arthritis), ShanghaiFudan-Zhangjiang Bio-Pharmaceutical, recombinant human interleukin-2recombinant TNF receptor 2-Fc fusion protein mutant, RG-6125, RhuDex,rifabutin with clarithromycin with clofazimine, rituximab, rituximabbiosimilar, rituximab follow-on biologic, RPI-78, SAN-300, sarilumab,SBI-087, seliciclib, SHR-0302, sirukumab, spebrutinib, SSS-07,KDDF-201110-06, Syn-1002, T-5224, TAB-08, tacrolimus, TAK-020, TAK-079,tarenflurbil (transdermal spraygel, skin disease/rheumatoid arthritis),MIKA Pharma/GALENpharma, technetium Tc 99m tilmanocept, technetium[99Tc]methylenediphosphonate, tenoxicam, Debio-0512, tocilizumab, tofacitinib,Trichuris suis ova, umbilical cord-derived mesenchymal stem cells (iv,RA/liver disease), Alliancells/Zhongyuan Union, ustekinumab, VAY-736,VB-201, WF-10, XmAb-5871, YHB-1411-2; 14-3-3 protein eta inhibitors,such as anti-AGX-020 mAbs (rheumatoid arthritis), Augurex;5-Lipoxygenase inhibitors, such as tenoxicam, darbufelone, tebufelone,licofelone, ZD-2138, etalocib, tenidap, tepoxalin, flobufen, SKF-86002,PGV-20229, L-708780, WY-28342, T-0757, T-0799, ZM-216800, L-699333,BU-4601A, SKF-104351, CI-986; Abl tyrosine kinase inhibitors, such asimatinib; ACTH receptor agonists, such as FAR-404, metenkefalin acetatewith tridecactide acetate; Adenosine A3 receptor agonists, such asCF-101; Adenosine deaminase inhibitors, such as cladribine, pentostatin,FR-221647; ADP ribosyl cyclase-1 modulators, such as indatuximabravtansine; ADP ribosylation factor 6 inhibitors, such as NAV-2729;Adrenocorticotrophic hormone ligands, such as corticotropin,Mallinckrodt, FAR-404, metenkefalin acetate with tridecactide acetate;Aggrecanase-2 inhibitors, such as GIBH-R-001-2; Albumin modulators, suchas ALX-0061, ONS-1210; APl transcription factor inhibitors, such asT-5224, tarenflurbil, SP-10030; Basigin inhibitors, such as ERG-240; Bcrprotein inhibitors, such as imatinib; B-lymphocyte antigen CD19inhibitors, such as XmAb-5871, MDX-1342; B-lymphocyte antigen CD20inhibitors, such as ocrelizumab, ofatumumab, rituximab, rituximabbiosimilar, veltuzumab, rituximab follow-on biologic, ocaratuzumab,BLX-301, IDEC-102, ABP-798, GP-2013, MK-8808, HLX-01, CT-P10, TL-011,PF-05280586, IBPM-001RX, IBI-301, AME-133v, BCD-020, BT-D004, SAIT-101;B-lymphocyte antigen CD20 modulators, such as rituximab biosimilar,SBI-087, TRU-015, DXL-625; B-lymphocyte stimulator ligand inhibitors,such as belimumab, RCT-18, blisibimod, tabalumab, atacicept, briobacept;Bradykinin receptor modulators, such as givinostat; BRAF geneinhibitors, such as binimetinib; Branched amino acid aminotransferase 1inhibitors, such as ERG-240; Bromodomain containing protein inhibitors,such as RVX-297, ZEN-003694; Btk tyrosine kinase inhibitors, such asacalabrutinib, HM-71224, spebrutinib, BTK inhibitor (rheumatoidarthritis), Humanwell Healthcare/Wuxi AppTech, BMS-986142, TAK-020,ONO-4059, TAS-5315, ABBV-105, AC-0025, RN-486, CG-026806, GDC-0834;Cadherin-11 antagonists, such as RG-6125; Calcineurin inhibitors, suchas HS-378, ciclosporin; Calcium channel inhibitors, such as RP-3128;Carbonic anhydrase inhibitors, such as polmacoxib; Cathepsin Kinhibitors, such as CRA-013783, T-5224, AM-3876, VEL-0230, NPI-2019;Cathepsin S inhibitors, such as MIV-247, AM-3876, RWJ-445380, NPI-2019;CCR1 chemokine antagonists, such as BX-471, BMS-817399, BI-638683,CCX-354, MLN-3701, MLN-3897, CP-481715, PS-375179; CCR2 chemokineantagonists, such as MK-0812, AZD-6942; CCR3 gene modulators, such asCM-102; CCR5 chemokine antagonists, such as maraviroc, OHR-118,NIBR-6465, AZD-5672, AZD-8566; CD126 antagonists, such as sarilumab;CD29 modulators, such as PF-06687234; CD3 modulators, such asotelixizumab; CD39 agonists, such as AAV5-CD39/CD73 (rheumatoidarthritis), Arthrogen; CD4 agonists, such as maraviroc; CD4 antagonists,such as tregalizumab, zanolimumab, MTRX-1011A, BW-4162W94, EP-1645,clenoliximab; CD40 ligand inhibitors, such as dapirolizumab pegol; CD40ligand receptor antagonists, such as BI-655064, anti-CD40-XTEN,teneliximab; CD40 ligand receptor modulators, such as CFZ-533; CD52antagonists, such as alemtuzumab; CD73 agonists, such as AAV5-CD39/CD73(rheumatoid arthritis), Arthrogen; CD79b modulators, such as MGD-010;CD80 antagonists, such as RhuDex, XENP-9523, ASP-2408, abataceptbiobetter; CD86 antagonists, such as ES-210, abatacept biosuperior,ASP-2408, XENP-9523; CD95 antagonists, such as DE-098, CS-9507; Celladhesion molecule inhibitors, such as natalizumab, alicaforsen,NPC-17923, TK-280, PD-144795; Choline kinase inhibitors, such as cholinekinase inhibitors (rheumatoid arthritis), UC San Diego; Clusterinstimulators, such as alemtuzumab; Complement C5 factor inhibitors, suchas eculizumab, antisense oligonucleotides (rheumatoid arthritis), LeidenUniversity Medical Center; Complement Factor stimulators, such asCM-101; C-reactive protein inhibitors, such as IB-RA (oral, rheumatoidarthritis), Innobioscience, ISIS-353512; CSF-1 antagonists, such asmasitinib, FPA-008, JNJ-27301937, JNJ-40346527, PLX-5622, CT-1578,PD-360324, JNJ-28312141; CXC10 chemokine ligand inhibitors, such as946414-98-8, BMS-936557; CXCR4 chemokine antagonists, such asplerixafor; Cyclin-dependent kinase inhibitor 1 inhibitors, such asCDK-1/2/5/7/9 inhibitors (cancer/tumorogenesis/rheumatoid arthritis),BioPatterns; Cyclin-dependent kinase-2 inhibitors, such as seliciclib,BP-14; Cyclin-dependent kinase-4 inhibitors, such as CDK-4/6 inhibitor(rheumatoid arthritis), Teijin; Cyclin-dependent kinase-5 inhibitors,such as BP-14; Cyclin-dependent kinase-6 inhibitors, such as CDK-4/6inhibitor (rheumatoid arthritis), Teijin; Cyclin-dependent kinase-7inhibitors, such as BP-14, seliciclib; Cyclin-dependent kinase-9inhibitors, such as BP-14, seliciclib; Cyclooxygenase 2 inhibitors, suchas celecoxib, etoricoxib, polmacoxib, laflunimus, etodolac, meloxicam,IB-RA (injectable, rheumatoid arthritis), Innobioscience, IB-RA (oral,rheumatoid arthritis), Innobioscience, SKLB-023, meloxicam, lumiracoxib;Cyclooxygenase 2 modulators, such as DRGT-46; Cyclooxygenase inhibitors,such as aceclofenac, diclofenac, imidazole salicylate, naproxcinod,naproxen etemesil, misoprostol with diclofenac, nabumetone, naproxenwith esomeprazole, naproxen with esomeprazole strontium, once-dailynaproxen (oral controlled release, pain), Alvogen, pelubiprofen,LY-210073, tenoxicam, licofelone, NS-398, bromfenac, L-746483,LY-255283, tenidap, tepoxalin, flobufen, ibuprofen, flurbiprofen,SKF-86002, SC-57666, WY-28342, CI-986, bermoprofen; Cytosolicphospholipase A2 inhibitors, such as AVX-002; Cytotoxic T-lymphocyteprotein-4 modulators, such as belatacept, ES-210; Cytotoxic T-lymphocyteprotein-4 stimulators, such as abatacept, abatacept biosimilar,BMS-188667; DHFR inhibitors, such as methotrexate, MPI-2505, MBP-Y003;Diamine acetyltransferase inhibitors, such as diminazene aceturate;Dihydroorotate dehydrogenase inhibitors, such as DHODH inhibitors(rheumatoid arthritis/autoimmune diseases), East China University ofScience and Technology, ASLAN-003, laflunimus, leflunomide, HWA-486,ABR-224050; Elongation factor 2 inhibitors, such as denileukin diftitox;Eotaxin 2 ligand inhibitors, such as CM-102; EP4 prostanoid receptorantagonists, such as CR-6086; Erythropoietin receptor agonists, such ascibinetide; Fas ligands, such as AP-300; FGF-2 ligand inhibitors, suchas RBM-007; FK506 binding protein-12 modulators, such as temsirolimus;Folate antagonists, such as methotrexate, MBP-Y003; Folate receptoragonists, such as folate receptor modulators (chimeric protein,cancer/rheumatoid arthritis), Proda Biotech; Folate receptor modulators,such as technetium (99mTc) etarfolatide; Fractalkine ligand inhibitors,such as E-6011; Fyn tyrosine kinase inhibitors, such as masitinib,laflunimus; G protein coupled receptor 15 antagonists, such as GPR15antagonists (rheumatoid arthritis/HIV-mediated enteropathy), Omeros;GABA A receptor modulators, such as laflunimus; Glucocorticoid agonists,such as prednisolone, fosdagrocorat; Glucocorticoid antagonists, such asREC-200; Glucocorticoid induced leucine zipper stimulators, such asART-G01; GM-CSF ligand inhibitors, such as namilumab, MORAb-022,lenzilumab; GM-CSF receptor antagonists, such as mavrilimumab; GM-CSFreceptor modulators, such as GSK-3196165; Growth regulated protein alphaligand inhibitors, such as T-5224; Hwith Kwith ATPase inhibitors, suchas naproxen with esomeprazole, naproxen with esomeprazole strontium,ketoprofen with omeprazole, KEO-25001, HC-1004, PN-40020; Histamine H4receptor antagonists, such as toreforant, GD-48; Histone deacetylaseinhibitors, such as givinostat, CHR-5154; Histone deacetylase-6inhibitors, such as CKD-506; HIV-1 gp120 protein inhibitors, such asmaraviroc; HLA class II antigen DQ-2 alpha modulators, such as NexVax2;HLA class II antigen inhibitors, such as HLA-DR1/DR4 inhibitors(rheumatoid arthritis), Provid; HLA class II antigen modulators, such asARG-301, recombinant T-cell receptor ligand (rheumatoid arthritis),Artielle; Hsp 70 family inhibitors, such as gusperimus trihydrochloride;Hypoxia inducible factor-1 inhibitors, such as 2-methoxyestradiol; IFNBgene stimulators, such as ART-102; I-kappa B kinase beta inhibitors,such as IMD-2560, IMD-0560; I-kappa B kinase inhibitors, such asbardoxolone methyl; IL-1 antagonists, such as rilonacept, IBPB-007-IL,antisense oligonucleotides (rheumatoid arthritis), Leiden UniversityMedical Center, recombinant human interleukin-1 receptor antagonist(rheumatoid arthritis), Shanghai Fudan-Zhangjiang Bio-Pharmaceutical;IL-10 agonists, such as peg-ilodecakin; IL-11 agonists, such asoprelvekin; IL-12 antagonists, such as ustekinumab, briakinumab, ddRNAitherapy (rheumatoid arthritis), Medistem/Benitec; IL-15 antagonists,such as AMG-714, BNZ-132-2; IL-17 antagonists, such as ixekizumab,secukinumab, KD-025; IL-17 receptor modulators, such as CNTO-6785; IL-2agonists, such as interleukin-2 follow-on biologic; IL-2 antagonists,such as IB-RA (injectable, rheumatoid arthritis), Innobioscience, IB-RA(oral, rheumatoid arthritis), Innobioscience, BNZ-132-2; IL-21antagonists, such as NN-8828, BNZ-132-2; IL-23 antagonists, such asustekinumab, briakinumab; IL-3 antagonists, such as anti-IL-3 mAbs(rheumatoid arthritis), University of Regensburg; IL-4 agonists, such asSER-130-AMI; IL-6 antagonists, such as olokizumab, clazakizumab,sirukumab, SA-237, tocilizumab, ALX-0061, FB-704A, OP-R003, peptide IL-6antagonist, MEDI-5117, T-5224, humanized anti-IL-6 mAb, tocilizumabbiosimilar, IL-6 neutralizing human antibodies, anti-IL6 antibody,RN-486, BLX-1002, AMG-220, FM-101, K-832, BLX-1025, esonarimod, TA-383;IL-6 receptor modulators, such as tocilizumab, tocilizumab biosimilar,RO-4877533; Immunoglobulin antagonists, such as iguratimod;Immunoglobulin G1 agonists, such as canakinumab, infliximab biobetter,infliximab biosimilar, BX-2922, STI-002, HF-1020; Immunoglobulin G1antagonists, such as YHB-1411-2; Immunoglobulin G1 modulators, such asCFZ-533, lenzilumab; Immunoglobulin G2 antagonists, such as denosumab;Immunoglobulin G2 modulators, such as PF-547659; Immunoglobulin gamma Fcreceptor II modulators, such as MGD-010; Immunoglobulin gamma Fcreceptor IIB antagonists, such as XmAb-5871; Immunoglobulin kappamodulators, such as lenzilumab; Immunoglobulin M antagonists, such asIB-RA (injectable, rheumatoid arthritis), Innobioscience, IB-RA (oral,rheumatoid arthritis), Innobioscience; Inducible nitric oxide synthaseinhibitors, such as SKLB-023; Inosine monophosphate dehydrogenaseinhibitors, such as mycophenolate mofetil; Insulin sensitizers, such asrosiglitazone, THR-0921, HE-3286, BLX-1002; Integrin alpha-1/beta-1antagonists, such as SAN-300; Integrin alpha-4/beta-1 antagonists, suchas natalizumab; Integrin antagonists, such as PEG-HM-3, CY-9652;Interferon beta ligands, such as recombinant interferon beta-1a, TA-383;Interferon gamma ligands, such as interferon gamma follow-on biologic;Interleukin 17A ligand inhibitors, such as ABT-122, bimekizumab,ABBV-257; Interleukin 17F ligand inhibitors, such as bimekizumab;Interleukin 23A inhibitors, such as guselkumab; Interleukin ligands,such as IBPB-007-IL; Interleukin receptor 17A antagonists, such asbrodalumab; Interleukin-1 beta ligand inhibitors, such as canakinumab,rilonacept, T-5224, gevokizumab, BLX-1002, LY-2189102, PMI-001, K-832,CDP-484; Interleukin-10 ligands, such as PF-06687234; Interleukin-2ligands, such as denileukin diftitox, recombinant interleukin-2,interleukin-2 follow-on biologic, recombinant human interleukin-2,interleukin-2 (injectable); Interleukin-4 ligands, such as Tetravil;Interleukin-6 ligand inhibitors, such as gerilimzumab, PF-4236921; Itktyrosine kinase inhibitors, such as ARN-4079; JAK tyrosine kinaseinhibitors, such as tofacitinib, SHR-0302, cerdulatinib, peficitinib,deuterated tofacitinib analog, SD-900, CVXL-0074; Jak1 tyrosine kinaseinhibitors, such as ABT-494, baricitinib, ruxolitinib, filgotinib,tofacitinib, itacitinib, peficitinib, NIP-585, CS-944X, YJC-50018,GLPG-0555, MRK-12; Jak2 tyrosine kinase inhibitors, such as baricitinib,ruxolitinib, CT-1578; JAK3 gene inhibitors, such as GBL-5b; Jak3tyrosine kinase inhibitors, such as decemotinib, tofacitinib,peficitinib, AC-0025, CS-944X, DNX-04042, MTF-003, ARN-4079, PS-020613;Jun N terminal kinase inhibitors, such as IQ-1S; KCNA voltage-gatedpotassium channel-3 modulators, such as MRAD-P1; Kelch like ECHassociated protein 1 modulators, such as dimethyl fumarate; Kit tyrosinekinase inhibitors, such as imatinib, masitinib; LanC like protein 2modulators, such as BT-11; LITAF gene inhibitors, such as GBL-5b;Lymphocyte function antigen-3 receptor antagonists, such as alefacept;Lyn tyrosine kinase inhibitors, such as masitinib; Macrophage mannosereceptor 1 modulators, such as technetium Tc 99m tilmanocept; MAdCAMinhibitors, such as PF-547659; MAP kinase modulators, such as SKLB-023;MAP3K2 gene inhibitors, such as GBL-5b; MAPKAPK5 inhibitors, such asGLPG-0259; Matrix metalloprotease inhibitors, such as GLPG-0259; MCL1gene inhibitors, such as seliciclib; MEK protein kinase inhibitors, suchas binimetinib, AD-GL0001; MEK-1 protein kinase inhibitors, such asbinimetinib; MEK-2 protein kinase inhibitors, such as binimetinib;Membrane copper amine oxidase inhibitors, such as BTT-1023, PRX-167700,vepalimomab; Metalloprotease-2 inhibitors, such as ERG-240;Metalloprotease-9 inhibitors, such as GS-5745, ERG-240; Midkine ligandinhibitors, such as CAB-102; Mitochondrial 10 kDa heat shock proteinstimulators, such as INV-103; mTOR complex 1 inhibitors, such aseverolimus; mTOR inhibitors, such as everolimus, temsirolimus; NAD ADPribosyltransferase stimulators, such as denileukin diftitox; NAMPT geneinhibitors, such as ART-D01; NF kappa B inhibitor stimulators, such asdenosumab; NFAT gene inhibitors, such as T-5224; NFE2L2 genestimulators, such as bardoxolone methyl; Nicotinic acetylcholinereceptor antagonists, such as RPI-78, RPI-MN; NK cell receptormodulators, such as masitinib; NKG2 A B activating NK receptorantagonists, such as monalizumab; NKG2 D activating NK receptorantagonists, such as NNC-0142-002; Nuclear erythroid 2-related factor 2stimulators, such as dimethyl fumarate; Nuclear factor kappa Binhibitors, such as bardoxolone methyl, IB-RA (injectable, rheumatoidarthritis), Innobioscience, dehydroxymethylepoxyquinomicin, HE-3286,IMD-0560, MP-42, tarenflurbil, VGX-1027, SKLB-023, SP-650003, MG-132,SIM-916, VGX-350, VGX-300, GIT-027, SP-100030, MLN-1145, NVP-IKK-005;Nuclear factor kappa B modulators, such as REM-1086; Nuclear factorkappa B p105 inhibitors, such as REM-1086; Opioid growth factor receptoragonists, such as metenkefalin acetate with tridecactide acetate,FAR-404; Opioid receptor delta antagonists, such as HS-378; Osteoclastdifferentiation factor antagonists, such as denosumab, cyclicpeptidomimetics (rheumatoid arthritis/osteoporosis), University ofMichigan; Osteoclast differentiation factor ligand inhibitors, such asdenosumab; Oxidoreductase inhibitors, such as etodolac, imidazolesalicylate; P2X7 purinoceptor agonists, such as givinostat; p38 MAPkinase alpha inhibitors, such as VX-745, BMS-582949 prodrugs,BMS-751324; p38 MAP kinase inhibitors, such as BCT-197, losmapimod,ARRY-797; PDE 4 inhibitors, such as apremilast; PDE 5 inhibitors, suchas PDE5 inhibitors (rheumatoid arthritis), University of Rochester; PDGFreceptor agonists, such as oprelvekin; PDGF receptor antagonists, suchas imatinib, masitinib; PDGF-B ligand inhibitors, such as SL-1026; PERKgene inhibitors, such as binimetinib; Phosphoinositide-3 kinase deltainhibitors, such as duvelisib, RP-6503, CT-732, INK-007, GNE-293;Phosphoinositide-3 kinase gamma inhibitors, such as duvelisib, RP-6503;Phospholipase A2 inhibitors, such as AVX-002, human secretedphospholipase A2 type IIA-integrin binding inhibiting peptides(rheumatoid arthritis/asthma/Alzheimer's disease/cancer), University ofCalifornia, Davis, AK-106, varespladib methyl, Ro-31-4493, BM-162353,Ro-23-9358, YM-26734; Platelet activating factor receptor antagonists,such as piperidone hydrochloridum; PPAR gamma agonists, such asrosiglitazone, THR-0921, rosiglitazone XR, etalocib; Programmed celldeath protein 1 modulators, such as INSIX RA; Prostaglandin D synthasestimulators, such as HF-0220; Protein arginine deiminase inhibitors,such as PAD inhibitors (rheumatoid arthritis), Leiden University MedicalCenter/LURIS; Protein tyrosine kinase inhibitors, such as leflunomide;PurH purine biosynthesis protein inhibitors, such as mycophenolatemofetil; Rho associated protein kinase 2 inhibitors, such as KD-025;Seprase inhibitors, such as anti-fibroblast-activation protein (FAP)antibody radiotracers (rheumatoid arthritis), Hoffmann-La Roche/RadboudUniversity; Signal transducer CD24 modulators, such as CD24-IgFc; Signaltransduction inhibitors, such as imatinib; Sodium glucose transporter-2inhibitors, such as THR-0921; Sphingosine 1 phosphate phosphatasemodulators, such as S1P modulators (oral, multiple sclerosis/ulcerativecolitis/rheumatoid arthritis), Akaal Pharma; STAT3 gene inhibitors, suchas bardoxolone methyl, vidofludimus; Superoxide dismutase stimulators,such as imisopasem manganese; SYK family tyrosine kinase inhibitors,such as MK-8457; Syk tyrosine kinase inhibitors, such as fostamatinib,entospletinib, KDDF-201110-06, HMPL-523, cerdulatinib, AB-8779, GS-9876,PRT-2607, CVXL-0074, CG-103065 and CG-026806; Syndecan-1 inhibitors,such as indatuximab ravtansine; T cell receptor antagonists, such as TCRinhibiting SCHOOL peptides (systemic/topical, rheumatoidarthritis/dermatitis/scleroderma), SignaBlok, CII modified peptide(rheumatoid arthritis), Peking University; T cell receptor modulators,such as ARG-301; T cell surface glycoprotein CD28 inhibitors, such asabatacept, belatacept, abatacept biosimilar, RhuDex, BMS-188667; T cellsurface glycoprotein CD28 stimulators, such as TAB-08; TAK1 bindingprotein modulators, such as epigallocatechin 3-gallate; Talinmodulators, such as short-form talin regulators (rheumatoid arthritis),KayteeBio; T-cell differentiation antigen CD6 inhibitors, such asitolizumab; T-cell surface glycoprotein CD8 inhibitors, such astregalizumab; Tenascin modulators, such as Tetravil; TGF beta agonists,such as tregalizumab; Thymulin agonists, such as Syn-1002; TLR-2antagonists, such as VB-201, P-13; TLR-4 antagonists, such as VB-201,P-13; TLR-9 antagonists, such as P-13; TNF alpha ligand inhibitors, suchas adalimumab biosimilar YHB-1411-2, adalimumab, infliximab, infliximabbiosimilar, recombinant humanized anti-TNF-alpha monoclonal antibody,certolizumab pegol, golimumab, ozoralizumab, AT-132, etanerceptbiosimilar, ISIS-104838, ISU-202, CT-P17, MB-612, Debio-0512, anti-TNFalpha human monoclonal antibody, infliximab biobetter, UB-721, KN-002,DA-3113, BX-2922, R-TPR-015, BOW-050, PF-06410293, CKD-760, CHS-1420,GS-071, ABP-710, STI-002, BOW-015, FKB-327, BAX-2200, HLX-03, BI-695501,CNTO-148, MYL-1401AABP-501, HOT-3010, BAX-2923, SCH-215596, ABT-D2E7,BAT-1406, XPro-1595, Atsttrin, SSS-07, golimumab biosimilar, TA-101,adalimumab follow-on biologic, BLX-1002, ABX-0401, TAQ-588, golimumabbiosimilar, TeHL-1, placulumab, PMI-001, tgAAV-TNFR:Fc, K-832,CYT-007-TNFQb, SSR-150106, PassTNF, Verigen, DOM-0200, DOM-0215,AME-527, anti-TNF-alpha mAb, GENZ-38167, BLX-1028, CYT-020-TNFQb,CC-1080, CC-1069; TNF alpha ligand modulators, such as MM-A01-01,CDP-571, camobucol; TNF antagonists, such as etanercept, certolizumabpegol, etanercept follow-on biologic, etanercept biosimilar, DNX-114,TNF antagonist with IL-12 antagonist (rheumatoid arthritis), Universityof Oxford, BN-006, SCB-131, pegsunercept, GBL-5b, ACE-772, onercept,DE-096, PN-0615, lenercept, ITF-1779, MDL-201112, BAX-2200, SCB-808,DA-3853, HD-203; TNF gene inhibitors, such as GIBH-R-001-2; TNF receptormodulators, such as recombinant TNF receptor 2-Fc fusion protein mutant,T-0001, tgAAV-TNFR:Fc; TNFSF11 gene inhibitors, such as denosumab;Transcription factor p65 inhibitors, such as REM-1086; Transcriptionfactor RelB inhibitors, such as REM-1086; Transferrin modulators, suchas methotrexate, MBP-Y003; Tumor necrosis factor 13C receptorantagonists, such as VAY-736; Tumor necrosis factor 15 ligandinhibitors, such as anti-TL1A antibodies (rheumatoidarthritis/inflammatory bowel disease), NIAMS; Tumor necrosis factorligand 13 inhibitors, such as atacicept; Tumor necrosis factor ligandinhibitors, such as ABBV-257, etanercept biosimilar, ABT-122; Type IIL-1 receptor antagonists, such as anakinra, anakinra biosimilar,anakinra follow-on biologic, AXXO; Type I TNF receptor antagonists, suchas NM-9405; Type II TNF receptor modulators, such as etanercept,SCB-131, etanercept biosimilar, etanercept follow-on biologic, BAX-2200,SCB-808, LBEC-0101, DMB-3853, DWP-422, BT-D001, DA-3853; UnspecifiedGPCR agonists, such as NCP-70X; VEGF receptor antagonists, such as2-methoxyestradiol and NSC-650853, SL-1026; VEGF-2 receptor antagonists,such as CG-026806; VEGF-2 receptor modulators, such as VEGFR2neutralizing antibody (rheumatoid arthritis), University of Rochester;VEGF-B ligand inhibitors, such as CSL-346; X-linked inhibitor ofapoptosis protein inhibitors, such as IAP inhibitors (oral),Pharmascience; and Zap70 tyrosine kinase inhibitors, such as MK-8457,CT-5332.

Combinations for Metabolic Diseases or Conditions

Examples of metabolic disorders include, without limitation, diabetes,including type I and type II diabetes, metabolic syndrome, dyslipidemia,obesity, glucose intolerance, hypertension, elevated serum cholesterol,and elevated triglycerides. Examples of therapeutic agents used to treatmetabolic disorders include antihypertensive agents and lipid loweringagents. Additional therapeutic agents used to treat metabolic disordersinclude insulin, sulfonylureas peroxisome proliferator activatedreceptor gamma (PPAR-γ) agonists, such as thiazolidinediones such aspioglitazones, biguanides, alpha-glucosidase inhibitors, Vitamin E andincretin mimetics. Thus, one aspect of the disclosure is a method oftreating a metabolic disease comprising administering a compound of thedisclosure in combination with one or more compounds useful for thetreatment of metabolic diseases to a subject, particularly a humansubject, in need thereof.

Pharmaceutical Compositions

While it is possible for the active ingredients to be administered aloneit may be preferable to present them as pharmaceutical formulations(compositions). The formulations, both for veterinary and for human use,of the invention comprise at least one active ingredient, as abovedefined, together with one or more acceptable carriers therefor andoptionally other therapeutic ingredients. The carrier(s) must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and physiologically innocuous to the recipientthereof.

The formulations include those suitable for the foregoing administrationroutes. The formulations may conveniently be presented in unit dosageform and may be prepared by any of the methods well known in the art ofpharmacy. Techniques and formulations generally are found in Remington'sPharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). Such methodsinclude the step of bringing into association the active ingredient withinactive ingredients (e.g., a carrier, pharmaceutical excipient, etc.)which constitutes one or more accessory ingredients. In general theformulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both, and then, if necessary, shaping the product.

In certain embodiments, formulations suitable for oral administrationare presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient.

In certain embodiments, the pharmaceutical formulations include one ormore compounds of the invention together with one or morepharmaceutically acceptable carriers or excipients and optionally othertherapeutic agents. Pharmaceutical formulations containing the activeingredient may be in any form suitable for the intended method ofadministration. When used for oral use for example, tablets, troches,lozenges, aqueous or oil suspensions, dispersible powders or granules,emulsions, hard or soft capsules, syrups or elixirs may be prepared.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsincluding sweetening agents, flavoring agents, coloring agents andpreserving agents, in order to provide a palatable preparation. Tabletscontaining the active ingredient in admixture with non-toxicpharmaceutically acceptable excipient which are suitable for manufactureof tablets are acceptable. These excipients may be, for example, inertdiluents, such as calcium or sodium carbonate, lactose, lactosemonohydrate, croscarmellose sodium, povidone, calcium or sodiumphosphate; granulating and disintegrating agents, such as maize starch,or alginic acid; binding agents, such as cellulose, microcrystallinecellulose, starch, gelatin or acacia; and lubricating agents, such asmagnesium stearate, stearic acid or talc. Tablets may be uncoated or maybe coated by known techniques including microencapsulation to delaydisintegration and adsorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearatealone or with a wax may be employed.

The amount of active ingredient that is combined with the inactiveingredients to produce a dosage form will vary depending upon the hosttreated and the particular mode of administration. For example, in someembodiments, a dosage form for oral administration to humans containsapproximately 1 to 1000 mg of active material formulated with anappropriate and convenient amount of carrier material (e.g., inactiveingredient or excipient material). In certain embodiments, the carriermaterial varies from about 5 to about 95% of the total compositions(weight:weight). In some embodiments, the pharmaceutical compositionsdescribed herein contain about 1 to 800 mg, 1 to 600 mg, 1 to 400 mg, 1to 200 mg, 1 to 100 mg or 1 to 50 mg of the compound of Formula I, or apharmaceutically acceptable salt thereof. In some embodiments, thepharmaceutical compositions described herein contain not more than about400 mg of the compound of Formula I. In some embodiments, thepharmaceutical compositions described herein contain about 100 mg of thecompound of Formula I, or a pharmaceutically acceptable salt thereof.

It should be understood that in addition to the ingredients particularlymentioned above the formulations disclosed herein may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

Veterinary compositions comprising at least one active ingredient asabove defined together with a veterinary carrier are further provided.

Veterinary carriers are materials useful for the purpose ofadministering the composition and may be solid, liquid or gaseousmaterials which are otherwise inert or acceptable in the veterinary artand are compatible with the active ingredient. These veterinarycompositions may be administered orally, parenterally or by any otherdesired route.

Effective dose of active ingredient depends at least on the nature ofthe condition being treated, toxicity, whether the compound is beingused prophylactically (lower doses), the method of delivery, and thepharmaceutical formulation, and will be determined by the clinicianusing conventional dose escalation studies.

Routes of Administration

One or more compounds of Formula I (herein referred to as the activeingredients), or a pharmaceutically acceptable salt thereof, areadministered by any route appropriate to the condition to be treated.Suitable routes include oral, rectal, nasal, topical (including buccaland sublingual), vaginal and parenteral (including subcutaneous,intramuscular, intravenous, intradermal, intrathecal and epidural), andthe like. It will be appreciated that the preferred route may vary withfor example the condition of the recipient. An advantage of thecompounds of this invention is that they are orally bioavailable and canbe dosed orally. Accordingly, in one embodiment, the pharmaceuticalcompositions described herein are oral dosage forms. In certainembodiments, the pharmaceutical compositions described herein are oralsolid dosage forms.

Formulation Example 1

Hard gelatin capsules containing the following ingredients are prepared:

Quantity Ingredient (mg/capsule) Active Ingredient 30.0 Starch 305.0Magnesium stearate 5.0

The above ingredients are mixed and filled into hard gelatin capsules.

Formulation Example 2

A tablet Formula is prepared using the ingredients below:

Quantity Ingredient (mg/tablet) Active Ingredient 25.0 Cellulose,microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0

The components are blended and compressed to form tablets.

Formulation Example 3

A dry powder inhaler formulation is prepared containing the followingcomponents:

Ingredient Weight % Active Ingredient 5 Lactose 95

The active ingredient is mixed with the lactose and the mixture is addedto a dry powder inhaling appliance.

Formulation Example 4

Tablets, each containing 30 mg of active ingredient, are prepared asfollows:

Quantity Ingredient (mg/tablet) Active Ingredient 30.0 mg Starch 45.0 mgMicrocrystalline cellulose 35.0 mg Polyvinylpyrrolidone 4.0 mg (as 10%solution in sterile water) Sodium carboxymethyl starch 4.5 mg Magnesiumstearate 0.5 mg Talc 1.0 mg Total 120 mg

The active ingredient, starch and cellulose are passed through a No. 20mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders, which are thenpassed through a 16 mesh U.S. sieve. The granules so produced are driedat 50° C. to 60° C. and passed through a 16 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate and talc, previously passedthrough a No. 30 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 120 mg.

Formulation Example 5

Suppositories, each containing 25 mg of active ingredient are made asfollows:

Ingredient Amount Active Ingredient   25 mg Saturated fatty acidglycerides to 2,000 mg

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2.0 g capacity and allowed to cool.

Formulation Example 6

Suspensions, each containing 50 mg of active ingredient per 5.0 mL doseare made as follows:

Ingredient Amount Active Ingredient 50.0 mg Xanthan gum 4.0 mg Sodiumcarboxymethyl cellulose (11%) Microcrystalline cellulose (89%) 50.0 mgSucrose 1.75 g Sodium benzoate 10.0 mg Flavor and Color q.v. Purifiedwater to 5.0 mL

The active ingredient, sucrose and xanthan gum are blended, passedthrough a No. 10 mesh U.S. sieve and then mixed with a previously madesolution of the microcrystalline cellulose and sodium carboxymethylcellulose in water. The sodium benzoate, flavor and color are dilutedwith some of the water and added with stirring. Sufficient water is thenadded to produce the required volume.

Formulation Example 7

A subcutaneous formulation may be prepared as follows:

Ingredient Quantity Active Ingredient 5.0 mg  Corn Oil 1.0 mL

Formulation Example 8

An injectable preparation is prepared having the following composition:

Ingredients Amount Active ingredient 2.0 mg/mL Mannitol, USP  50 mg/mLGluconic acid, USP q.s. (pH 5-6) water (distilled, sterile) q.s. to 1.0mL Nitrogen Gas, NF q.s.

Formulation Example 9

A topical preparation is prepared having the following composition:

Ingredients grams Active ingredient 0.2-10 Span 60 2.0 Tween 60 2.0Mineral oil 5.0 Petrolatum 0.10 Methyl paraben 0.15 Propyl paraben 0.05BHA (butylated hydroxy anisole) 0.01 Water q.s. to 100

All of the above ingredients, except water, are combined and heated to60° C. with stirring. A sufficient quantity of water at 60° C. is thenadded with vigorous stirring to emulsify the ingredients and water thenadded q.s. 100 g.

Formulation Example 10

Sustained Release Composition

Ingredient Weight Range % Active ingredient 50-95 Microcrystallinecellulose (filler)  1-35 Methacrylic acid copolymer  1-35 Sodiumhydroxide 0.1-1.0 Hydroxypropyl methylcellulose 0.5-5.0 Magnesiumstearate 0.5-5.0

Sustained release formulations of this disclosure may be prepared asfollows: compound and pH-dependent binder and any optional excipientsare intimately mixed (dry-blended). The dry-blended mixture is thengranulated in the presence of an aqueous solution of a strong base whichis sprayed into the blended powder. The granulate is dried, screened,mixed with optional lubricants (such as talc or magnesium stearate) andcompressed into tablets. Preferred aqueous solutions of strong bases aresolutions of alkali metal hydroxides, such as sodium or potassiumhydroxide, preferably sodium hydroxide, in water (optionally containingup to 25% of water-miscible solvents such as lower alcohols).

The resulting tablets may be coated with an optional film-forming agent,for identification, taste-masking purposes and to improve ease ofswallowing. The film forming agent will typically be present in anamount ranging from between 2% and 4% of the tablet weight. Suitablefilm-forming agents are well known to the art and include hydroxypropylmethylcellulose, cationic methacrylate copolymers (dimethylaminoethylmethacrylate/methyl-butyl methacrylate copolymers—Eudragit® E—Röhm.Pharma) and the like. These film-forming agents may optionally containcolorants, plasticizers and other supplemental ingredients.

The compressed tablets preferably have a hardness sufficient towithstand 8 Kp compression. The tablet size will depend primarily uponthe amount of compound in the tablet. The tablets will include from 300to 1100 mg of compound free base. Preferably, the tablets will includeamounts of compound free base ranging from 400-600 mg, 650-850 mg and900-1100 mg.

In order to influence the dissolution rate, the time during which thecompound containing powder is wet mixed is controlled. Preferably thetotal powder mix time, i.e., the time during which the powder is exposedto sodium hydroxide solution, will range from 1 to 10 minutes andpreferably from 2 to 5 minutes. Following granulation, the particles areremoved from the granulator and placed in a fluid bed dryer for dryingat about 60° C.

Formulation Example 11

A tablet Formula Is prepared using the ingredients below:

Quantity Ingredient (mg/tablet) Active Ingredient 300.0 Cellulose,microcrystalline 100.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0

The components are blended and compressed to form tablets.

EXAMPLES

The following examples are included to demonstrate specific embodimentsof the disclosure. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples which follow representtechniques to function well in the practice of the disclosure, and thuscan be considered to constitute specific modes for its practice.However, those of skill in the art should, in light of the presentdisclosure, appreciate that many changes can be made in the specificembodiments which are disclosed and still obtain a like or similarresult without departing from the spirit and scope of the disclosure.

LIST OF ABBREVIATIONS AND ACRONYMS

Abbreviation Meaning ° C. Degree Celsius Ac Acetyl aq. Aqueous ATPAdenosine triphosphate B₂Pin₂ Bis(pinacolato)diboron BOCtert-Butoxycarbonyl Br Broad BSA Bovine serum albumin d Doublet DCMDichloromethane dd Doublet of doublets ddd Doublet of doublet ofdoublets DIPEA N,N-Diisopropylethylamine (Hünig's Base) DMADimethylacetamide DME 1,2-Dimethoxyethane DMF Dimethylformamide DMSODimethylsulfoxide dt Doublet-triplet DTT Dithiothreitol (Cleland'sreagent) EC₅₀ The half maximal effective concentration EDC1-(3-dimethylaminopropyl)-3-ethylcarbodiimide EDTAEthylenediaminetetraacetic acid EGFR Epidermal growth factor receptor EqEquivalents ES/MS Electrospray mass spectrometry Et Ethyl EtOAc Ethylacetate EtOH Ethanol (Ethyl alcohol) FBS Fetal bovine serum g Grams HATU1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate HEPES 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid HCl Hydrochloric acid HPLC High pressure liquidchromatography Hrs Hours HTRF ® Homogeneous time resolved fluorescence,a registered trademark of Cisbio Bioassays, parc marcel boiteux 30200codolet, France Hz Hertz IBD Inflammatory bowel disease IC₅₀Half-maximal inhibitory concentration i-pr Isopropyl J Coupling constant(MHz) K₃PO₄ Tripotasium phosphate KOtBu Potassium tert-butoxide KOAcPotassium Acetate LCMS Liquid chromatography-mass spectrometryLawesson's 2,4-Bis-(4-methoxyphenyl)-1,3-dithia-2,4- Reagentdiphosphetane 2,4-disulfide Li HMDS Lithium bis(trimethylsilyl)amideLiOH Lithium hydroxide LiI Lithium iodide LPS Lipopolysaccharide M Molarm multiplet M+ Mass peak M + H+ Mass peak plus hydrogen Me Methyl MeCNAcetonitrile MeOH Methanol (Methyl alcohol) MeLi Methyllithium MeMgXMethylmagnesium halide (Grignard reagent), where X is Fluoro, Chloro,Bromo or Iodo Me₆Sn₂ Hexamethyldistannane (hexamethylditin) mg MilligramMgSO₄ Magnesium sulfate MHz Megahertz Min Minute ml/mL Milliliter mMMillimolar mmol Millimole MS Mass spectroscopy MsCl Mesyl chloride NBSN-Bromosuccinimide n- Normal nBu/Bu n-Butyl (normal Butyl) n-BuLin-Butyl Lithium NaH Sodium hydride NaHCO₃ Sodium bicarbonate NaN₃ Sodiumazide Na₃PO₄ Trisodium phosphate Na₂SO₄ Sodium sulfate nL Nanoliter nmNanometer NMP 1-methylpyrrolidin-2-one NMR Nuclear magnetic resonanceNP-40 Nonyl phenoxypolyethoxylethanol Pd-PEPPSI ™-[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2- IPentylidene](3-chloropyridyl)palladium(II) dichloride Pen-StrepPenicillin-Streptomycin (5,000 units of penicillin G sodium salt, and5,000 μg streptomycin sulfate in 0.85% saline) Ph Phenyl q Quartet q.s.Quantity sufficient to achieve a stated function RP Reverse phase RPMIRoswell Park Memorial Institute medium Rt Room temperature s Singletsat. Saturated Selectfluor ® 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis (a trademark of Air Products andChemicals) SFC Supercritical fluid chromatography SiliaMetS ®Silica-based Palladium scavenger, registered Thiol trademark ofSilicycle T Triplet THF Tetrahydrofuran TFA Trifluoroacetic acid XPhosPd G3 (2-Dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′- biphenyl)]palladium(II)methanesulfonate

Experimental Procedures Synthesis of Intermediates Preparation ofIntermediate I-1

3,3-Diethoxy-2-formylpropionitrile Potassium Salt (I-1C)

To a stirred solution of 3,3-diethoxypropane-nitrile (I-1A, 283.80 g,1.98 moles) and methyl formate (I-1B, 148.80 g, 2.48 moles) in anhydrousTHF (1.1 L) at 10° C. was added 1.0 M potassium tert-butoxide in THF(2.2 L, 2.2 moles). The temperature was maintained in the range of 10°C. to 15° C. throughout the 45 minute addition. Following the addition,the resulting slurry was stirred for 2 hours at ambient temperature.Hexane (400 mL) was then added and stirring was continued for another 20min. The slurry was filtered and the cake washed with 1/1 hexanes/THFand dried overnight at 60° C. in a vacuum oven to provide I-1C. ¹H-NMR(CD₃OD) was consistent with the desired structure.

Pyrrolo[1,2-b]pyridazine-3-carbonitrile (I-1E)

A stirred suspension of 3,3-diethoxy-2-formylpropionitrile potassiumsalt (I-1C, 5.10 g, 24.36 mmol) was cooled to 0° C., and concentratedHCl (7.11 mL, 85.26 mmol) was added dropwise at such a rate that theinternal temperature of the reaction did not go above 20° C. Afteraddition was complete, the reaction was stirred at room temperature for20 minutes. To this reaction mixture was added a solution of1-aminopyrrole (I-1D, 1.00 g, 12.18 mmol) in methanol (4.0 mL). Afteraddition, the reaction mixture was refluxed at 90° C. for 2 hours. Whenheating was complete, the reaction was cooled to room temperature andconcentrated to about half of the original volume. Saturated aqueoussodium bicarbonate was added carefully to the resulting residue untilbubbling stopped. The solution was extracted with two portions of ethylacetate. The combined organic layers were dried over sodium sulfate,filtered, concentrated in vacuo, and the resulting residue was purifiedby silica gel chromatography (eluent: EtOAc/hexanes) to provide I-1E.

1H NMR (400 MHz, Chloroform-d) δ 8.16-8.03 (m, 2H), 7.93 (ddd, J=2.6,1.4, 0.6 Hz, 1H), 7.04 (dd, J=4.5, 2.7 Hz, 1H), 6.84 (dd, J=4.6, 1.4 Hz,1H).

7-bromopyrrolo[1,2-b]pyridazine-3-carbonitrile (I-1F)

To a solution of pyrrolo[1,2-b]pyridazine-3-carbonitrile (I-1E, 840.0mg, 5.9 mmol) in MeCN (30 mL) at room temperature was addedN-bromosuccinimide in one portion. The reaction was stirred at roomtemperature for 30 minutes then poured into saturated aqueous sodiumbicarbonate. The solution was concentrated in vacuo to remove theacetonitrile. The resulting aqueous layer was extracted with threeportions of EtOAc. The combined organic layers were dried over sodiumsulfate, filtered, concentrated in vacuo, and purified by silica gelchromatography (eluent: EtOAc/hexanes) to provide I-1F.

1H NMR (400 MHz, Chloroform-d) δ 8.28 (d, J=2.1 Hz, 1H), 8.10 (d, J=2.1Hz, 1H), 7.12 (d, J=4.8 Hz, 1H), 6.93 (d, J=4.8 Hz, 1H).

7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(I-1)

A microwave vial was charged with7-bromopyrrolo[1,2-b]pyridazine-3-carbonitrile (I-1F, 416.5 mg, 1.9mmol), bis(pinacolato)diboron (762.1 mg, 3.0 mmol), potassium acetate(552.3 mg, 5.6 mmol), and bis(triphenylphosphine)palladium(II)dichloride (65.8 mg, 0.094 mmol). Dioxane (8.0 mL) and DMF (4.0 mL) wereadded, and the reaction mixture was degassed with bubbling argon for 2minutes. The vial was sealed and the reaction was heated at 120° C. in amicrowave reactor for 60 minutes. After cooling, the reaction mixturewas filtered and concentrated in vacuo. The resulting residue waspartitioned between EtOAc and water. The aqueous layer was extractedwith a second portion of EtOAc, and the combined organic layers weredried over sodium sulfate, filtered through a plug of Celite, andconcentrated in vacuo. The resulting residue was purified by silica gelchromatography (eluent: EtOAc/hexanes) to provide I-1.

1H NMR (400 MHz, Chloroform-d) δ 8.31 (d, J=2.3 Hz, 1H), 8.14 (d, J=2.2Hz, 1H), 7.52 (d, J=4.6 Hz, 1H), 6.84 (d, J=4.6 Hz, 1H), 1.41 (s, 12H).

Preparation of Intermediate I-2

Tert-Butyl(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclohex-3-en-1-yl)carbamate

4-((tert-butoxycarbonyl)amino)cyclohex-1-en-1-yltrifluoromethanesulfonate (3.52 g, 10.2 mmol),1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(3.11 g, 12.7 mmol), Pd(OAc)₂ (0.11 g, 0.51 mmol),butyldi-1-adamantylphosphine (0.37 g, 1.02 mmol), and K₂CO₃ (2.82 g,10.4 mmol) were combined in a sealed tube along with DME (20 mL) andwater (10 mL) and the resulting slurry was degassed with argon thenheated at 80° C. for 16 h. The reaction contents were diluted with EtOAc(70 mL), washed with brine (1×15 mL), and dried over MgSO₄. The cruderesidue was then purified via silica gel chromatography (eluent:EtOAc/hexanes) to give the product tert-butyl(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclohex-3-en-1-yl)carbamate.

ES/MS: 258.0 (M+H⁺).

4-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclohexan-1-amine hydrochloride(I-2)

A suspension of tert-butyl(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclohex-3-en-1-yl)carbamate(0.23 g, 0.75 mmol) in EtOH (15 mL) was degassed with argon and vacuum.Pd/C (10%, 91 mg, 0.086 mmol) was added and the mixture was stirred witha balloon of H₂ overnight. The reaction was filtered over a Celite plug,rinsed with EtOAc and the filtrate was concentrated to give tert-butyl(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclohexyl)carbamate which wascarried forward without further purification assuming quantitativeyield. To a solution of tert-butyl(4-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclohexyl)carbamate (0.24 g,0.75 mmol) in DCM (6 mL) was added HCl (4.0M in dioxane, 3 mL, 12 mmol)and the resulting solution stirred at room temperature for 16 h. Uponcompletion the reaction mixture was concentrated to dryness to give4-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclohexan-1-amine hydrochloride(I-2) which was used without further purification.

ES/MS: 216.1 (M+H⁺).

Preparation of Intermediate I-3 to I-12

Intermediates I-3 through I-12 were prepared in the manner described forI-2 substituting1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolewith the appropriately substituted heteroaryl boronic ester.

Preparation of Intermediate I-13

Tert-Butyl(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)cyclohex-3-en-1-yl)carbamate

tert-butyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)carbamate(0.60 g, 1.86 mmol), 1-(difluoromethyl)-3-iodo-1H-pyrazole (0.50 g, 2.05mmol), Pd(OAc)₂ (22 mg, 0.098 mmol), butyldi-1-adamantylphosphine (78mg, 0.22 mmol), and K₂CO₃ (0.51 g, 3.71 mmol) were combined in a sealedtube along with DME (10 mL) and water (5 mL) and the resulting slurrywas degassed with argon then heated at 80° C. for 18 h. The reactioncontents were diluted with EtOAc (40 mL), washed with brine (1×10 mL),and dried over MgSO₄. The crude residue was then purified via silica gelchromatography (eluent: EtOAc/hexanes) to give the product tert-butyl(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)cyclohex-3-en-1-yl)carbamate.

ES/MS: 313.7 (M+H⁺).

4-(1-(difluoromethyl)-1H-pyrazol-3-yl)cyclohexan-1-amine hydrochloride(I-13)

A suspension of tert-butyl(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)cyclohex-3-en-1-yl)carbamate(0.50 g, 0.1.60 mmol) in EtOH (15 mL) was degassed with argon andvacuum. Pd/C (10%, 85 mg, 0.080 mmol) was added and the mixture wasstirred with a balloon of H₂ overnight. The reaction was filtered over aCelite plug, rinsed with EtOAc and the filtrate was concentrated to givetert-butyl (4-(1-(difluoromethyl)-1H-pyrazol-3-yl)cyclohexyl)carbamatewhich was carried forward without further purification assumingquantitative yield. To a solution of tert-butyl(4-(1-(difluoromethyl)-1H-pyrazol-3-yl)cyclohexyl)carbamate (0.50 g,1.58 mmol) in DCM (10 mL) was added HCl (4.0M in dioxane, 2.9 mL, 11.6mmol) and the resulting solution stirred at room temperature for 16 h.Upon completion the reaction mixture was concentrated to dryness to give4-(1-(difluoromethyl)-1H-pyrazol-3-yl)cyclohexan-1-amine hydrochloride(I-13) which was used without further purification.

Preparation of Intermediates I-14 to I-23

Intermediates I-14 through I-23 were prepared in the manner describedfor I-13 substituting 1-(difluoromethyl)-3-iodo-1H-pyrazole with theappropriately substituted heteroaryl bromide or iodide.

Preparation of Intermediate I-24

Tert-Butyl ((1r,4r)-4-(hydrazinecarbonyl)cyclohexyl)carbamate

To a solution of(1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid(10.0 g, 41.1 mmol) in THF (360 mL) was added 1,1′-carbonyldiimidazole(10.7 g, 65.8 mmol) as a single portion and the resulting mixturestirred for 16 h at room temperature. Hydrazine hydrate (10.0 mL, 206mmol) was then added as a single portion. After 15 minutes approximately200 mL THF was removed by rotary evaporation and the resulting slurryfiltered rinsing with THF. The solid was dried under vacuum to givetert-butyl ((1r,4r)-4-(hydrazinecarbonyl)cyclohexyl)carbamate which wasused without further purification.

ES/MS: 202.2 (M+H⁺).

Tert-Butyl((1r,4r)-4-(2-(2,2-difluoroacetyl)hydrazine-1-carbonyl)cyclohexyl)carbamate

To a solution of tert-butyl((1r,4r)-4-(hydrazinecarbonyl)cyclohexyl)carbamate (1.50 g, 5.83 mmol)and diisopropylethylamine (2.6 mL, 14.9 mmol) in THF (20 mL) was addeddifluoroacetic anhydride (0.93 mL, 7.43 mmol) and the reaction mixtureallowed to stir at room temperature. After 30 minutes additionaldifluoroacetic anhydride (0.40 mL, 3.20 mmol) was added and the reactionmixture allowed to stir for 30 minutes. The reaction mixture was thenpoured into water (20 mL), extracted with EtOAc (2×40 mL), washed withbrine (1×15 mL), dried over MgSO₄, filtered and concentrated to givecrude tert-butyl((1r,4r)-4-(2-(2,2-difluoroacetyl)hydrazine-1-carbonyl)cyclohexyl)carbamatewhich was used without further purification.

ES/MS: 280.0 (M+H⁺).

Tert-Butyl((1r,4r)-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)cyclohexyl)carbamate

To a solution of tert-butyl((1r,4r)-4-(2-(2,2-difluoroacetyl)hydrazine-1-carbonyl)cyclohexyl)carbamate(1.66 g, 4.96 mmol) in dry acetonitrile (40 mL) was added sequentiallytriphenylphosphine (3.90 g, 14.9 mmol), hexachloroethane (1.76 g, 7.34mmol) and diisopropylethylamine (5.2 mL, 29.7 mmol) and the resultingsolution allowed to stir for 15 minutes at room temperature. Uponcompletion the reaction mixture was poured into saturated aqueous NH₄Cl(30 mL, and extracted with EtOAc (2×60 mL). The combined organics werewashed with brine (1×15 mL), dried over MgSO₄, filtered and concentratedto give a crude residue which was further purified using silica gelchromatography (eluent: EtOAc/hexanes) to give the product tert-butyl((1r,4r)-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)cyclohexyl)carbamate.

(1r,4r)-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)cyclohexan-1-aminehydrochloride (I-24)

Tert-butyl((1r,4r)-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)cyclohexyl)carbamate(1.26 g, 3.96 mmol) was dissolved in HCl solution (4.0M in dioxane, 12mL, 48 mmol) and the resulting mixture was stirred in a preheated 50° C.heating block for 30 minutes. Upon completion the suspension wasfiltered directly washing with dioxane (1×4 mL) and the solid driedunder vacuum to give(1r,4r)-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)cyclohexan-1-aminehydrochloride (I-24) which was used without further purification.

ES/MS: 218.0 (M+H⁺).

Preparation of Intermediates I-25 to I-29

Intermediates I-25 through I-29 were prepared in the manner describedfor I-24 substituting(1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid withthe appropriately substituted carboxylic acid.

Preparation of Intermediate I-30

Intermediate I-30 was prepared in the manner described for I-24,substituting difluoroacetic anhydride with 2-methoxyacetyl chloride inthe second step.

Preparation of Intermediate I-31

Intermediate I-31 was prepared in the manner described for I-24,substituting difluoroacetic anhydride with cyclopropane carbonylchloride in the second step.

Preparation of Intermediate I-32

(1r,4r)-4-(5-methyl-1,3,4-oxadiazol-2-yl)cyclohexan-1-aminehydrochloride

To a solution of tert-butyl((1r,4r)-4-(hydrazinecarbonyl)cyclohexyl)carbamate (0.15 g, 0.58 mmol)in triethylorthoacetate (2 mL) was added catalytic acetic acid (0.05 mL)and the resulting solution heated to 125° C. for 4 h. The reactionmixture was concentrated directly and the resulting crude tert-butyl((1r,4r)-4-(5-methyl-1,3,4-oxadiazol-2-yl)cyclohexyl)carbamate wasdissolved in HCl solution (4.0M in dioxane, 3 mL, 12 mmol) and stirredfor 12 h at room temperature. The reaction mixture was concentrateddirectly and the resulting(1r,4r)-4-(5-methyl-1,3,4-oxadiazol-2-yl)cyclohexan-1-aminehydrochloride was used without further purification.

ES/MS: 182.0 (M+H⁺).

Preparation of Intermediate I-33

Tert-Butyl((1r,4r)-4-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)cyclohexyl)carbamate

To a solution of tert-butyl((1r,4r)-4-(2-(2,2-difluoroacetyl)hydrazine-1-carbonyl)cyclohexyl)carbamate(0.21 g, 0.63 mmol) in THF (10 mL) was added Lawesson's reagent (0.30 g,0.75 mmol) and the resulting solution heated at 50° C. for 16 h. Uponcompletion the reaction mixture was poured into water (10 mL, extractedwith EtOAc (2×30 mL), washed with brine (10 mL), dried over MgSO₄ andconcentrated. The crude residue was purified using silica gelchromatography (eluent: EtOAc/hexanes) to give the product tert-butyl((1r,4r)-4-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)cyclohexyl)carbamate.

ES/MS: 333.9 (M+H⁺).

(1r,4r)-4-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)cyclohexan-1-aminehydrochloride (I-33)

tert-butyl((1r,4r)-4-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)cyclohexyl)carbamate(0.31 g, 0.39 mmol) was dissolved in HCl solution (4.0M in dioxane, 12mL, 48 mmol) and the resulting mixture was stirred at room temperaturefor 1 h. Upon completion the reaction contents were concentrated anddried under vacuum to give(1r,4r)-4-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)cyclohexan-1-aminehydrochloride (I-33) which was used without further purification.

ES/MS: 234.0 (M+H⁺).

Preparation of Intermediate I-34

Intermediate I-34 was prepared in the manner described for intermediateI-33 substituting tert-butyl((1r,4r)-4-(2-(2,2-difluoroacetyl)hydrazine-1-carbonyl)cyclohexyl)carbamatewith tert-butyl ((1r,4r)-4-(2-acetylhydrazine-1-carbonyl)cyclohexyl)carbamate in the firststep.

Preparation of Intermediates I-35 and I-36

Intermediates I-35 and I-36 were prepared in the manner described forintermediate I-32 substituting(1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid with4-((tert-butoxycarbonyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid and4-((tert-butoxycarbonyl)amino)-2-oxabicyclo[2.2.2]octane-1-carboxylicacid respectively.

Preparation of Intermediate I-37

4-((tert-butoxycarbonyl)amino)-2-oxabicyclo[2.2.2]octane-1-carboxylicacid (I-37)

To a solution of tert-butyl(1-formyl-2-oxabicyclo[2.2.2]octan-4-yl)carbamate (1.00 g, 3.92 mmol) inTHF (10 mL) and tBuOH (10 mL) was added 2-methyl-2-butene (8.3 mL, 78.3mmol) followed by NaH₂PO₄ (3.76 g, 31.3 mmol) as a solution in water (5mL) and finally sodium chlorite (1.06 g, 11.8 mmol) as a solution inwater (5 mL). After 16 h stirring at room temperature the reactionmixture was poured into saturated aqueous NH₄Cl (15 mL), and extractedwith EtOAc (2×40 mL). The combined organics were washed with brine (10mL), dried over MgSO₄, and concentrated to give4-((tert-butoxycarbonyl)amino)-2-oxabicyclo[2.2.2]octane-1-carboxylicacid (I-37) which was used without further purification.

ES/MS: 216.0 (M+H⁺).

Preparation of Intermediate I-38

(1r,4r)-4-(oxazol-5-yl)cyclohexan-1-amine Hydrochloride (I-38)

To a solution of tert-butyl (4-formylbicyclo[2.2.2]octan-1-yl)carbamate(0.80 g, 3.16 mmol) in MeOH (14 mL) was addedp-toluenesulfonylmethylisocyanide (0.74 g, 3.79 mmol) and the resultingmixture heated at 85° C. for 12 hours. The mixture was poured into water(20 mL) and extracted with EtOAc (2×40 mL). The combined organic layerswere dried over MgSO₄, filtered and concentrated. The resulting cruderesidue was purified by silica gel chromatography (eluent:EtOAc/hexanes) to give tert-butyl(4-(oxazol-5-yl)bicyclo[2.2.2]octan-1-yl)carbamate. This was thendissolved in HCl (4.0M in dioxane, 3 mL, 12 mmol) and stirred at roomtemperature for 3 hours after which the reaction mixture wasconcentrated to dryness directly to give(1r,4r)-4-(oxazol-5-yl)cyclohexan-1-amine hydrochloride (I-38) which wasused without further purification.

Preparation of Intermediate I-39

methyl(1s,4s)-4-((tert-butoxycarbonyl)amino)-1-fluorocyclohexane-1-carboxylate

To a solution/suspension of methyl(1s,4s)-4-amino-1-fluorocyclohexane-1-carboxylate (1.00 g, 4.73 mmol) inDCM (10 mL) at 0° C. was added diisopropylethylamine (1.8 mL, 10.4 mmol)followed by Di-tert-butyl dicarbonate (1.13 g, 5.20 mmol). After 2 hstirring at 0° C. The reaction mixture was poured into saturated aqueousNH₄Cl (15 mL) and extracted with EtOAc (2×40 mL). The combined organicswere washed with brine (1×15 mL), dried over MgSO₄ and concentrated togive methyl(1s,4s)-4-((tert-butoxycarbonyl)amino)-1-fluorocyclohexane-1-carboxylatewhich was used without further purification.

ES/MS: 219.9 (M+H⁺).

(1s,4s)-4-((tert-butoxycarbonyl)amino)-1-fluorocyclohexane-1-carboxylicacid (I-39)

To a solution of methyl(1s,4s)-4-((tert-butoxycarbonyl)amino)-1-fluorocyclohexane-1-carboxylate(1.30 g, 4.72 mmol) in EtOH (10 mL) was added lithium hydroxide (0.34 g,14.2 mmol) as a solution in water (4 mL) and the resulting solutionstirred at room temperature for 3 h. Upon completion the EtOH wasremoved by rotary evaporation and the resulting aqueous solution wasacidified to pH ˜2-3 using aqueous 1.0M HCl. The aqueous was thenextracted with EtOAc (3×30 mL) and the combined organics washed withbrine (1×15 mL), dried over MgSO₄ and concentrated to give(1s,4s)-4-((tert-butoxycarbonyl)amino)-1-fluorocyclohexane-1-carboxylicacid (I-39) which was used without further purification.

ES/MS: 206.0 (M+H⁺).

Preparation of Intermediate I-40

Tert-Butyl ((1r,4r)-4-(N-hydroxycarbamimidoyl)cyclohexyl)carbamate

DMSO (40 mL) was added to hydroxylamine hydrochloride (1.55 g, 22.3mmol) and the resulting mixture was heated to 40° C. for 30 minutes.NaHCO₃ (1.87 g, 22.3 mmol) was added as a single portion and the mixturethen heated at 50° C. for 1 h at which point a solution of tert-butyl((1r,4r)-4-cyanocyclohexyl)carbamate (0.50 g, 2.23 mmol) in DMSO (40 mL)was added and the reaction mixture heated at 90° C. for 16 h. Aftercooling, the reaction mixture was poured into water (150 mL) andextracted with EtOAc (2×225 mL). The combined organic layers were washedwith water (2×10 mL, brine (1×50 mL), dried over MgSO₄ and concentratedto give tert-butyl((1r,4r)-4-(N-hydroxycarbamimidoyl)cyclohexyl)carbamate which was usedwithout further purification.

(1r,4r)-4-(5-methyl-1,2,4-oxadiazol-3-yl)cyclohexan-1-amine (I-40)

To a solution of tert-butyl((1r,4r)-4-(N-hydroxycarbamimidoyl)cyclohexyl)carbamate (0.20 g, 0.78mmol) in acetonitrile (5 mL) was added sequentially p-toluenesulfonicacid (44 mg, 0.23 mmol) and ZnCl₂ (32 mg, 0.23 mmol). The resultingreaction mixture was heated at 70° C. for 6 h, poured into saturatedaqueous NaHCO₃ (5 mL, and extracted with EtOAc (2×25 mL). The combinedorganic layers were washed with brine (5 mL), dried over MgSO₄ andconcentrated to give(1r,4r)-4-(5-methyl-1,2,4-oxadiazol-3-yl)cyclohexan-1-amine (I-40) whichwas used without further purification.

Preparation of Intermediate I-41

Intermediate I-41 was prepared in the manner described for I-2substituting1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolewith2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

Preparation of Intermediate I-42

Tert-Butyl ((1r,4r)-4-(2H-4l4-tetrazol-4-yl)cyclohexyl)carbamate (I-42B)

To a solution of tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (I-42A,1000 mg, 4.67 mmol), sodium azide (306 mg, 4.407 mmol), and trimethylorthoformate (2350 μl, 21.44 mmol), was added AcOH (3 mL). The reactionwas heated at 70 deg for 48 hr. The reaction was diluted with water andcarefully neutralized with saturated NaHCO₃ solution. The resultingprecipitate was air-dried to give I-42B.

ES/MS: 267.9 (M⁺).

1H NMR (400 MHz, Chloroform-d) δ 8.60 (s, 1H), 4.51 (ddt, J=12.1, 7.9,3.9 Hz, 1H), 3.60 (s, 1H), 2.32 (dd, J=32.5, 13.1 Hz, 4H), 1.97 (qd,J=12.9, 3.5 Hz, 2H), 1.59 (s, 3H), 1.48 (s, 9H), 1.39 (td, J=13.1, 12.5,3.4 Hz, 2H).

(1r,4r)-4-(1H-tetrazol-1-yl)cyclohexan-1-amine hydrochloride (I-42)

To a solution of tert-butyl((1r,4r)-4-(2H-4l4-tetrazol-4-yl)cyclohexyl)carbamate (I-42B, 467.5 mg,1.749 mmol) in DCM (10 mL) was added HCl (3.0 mL, 4.0M in dioxane). Thereaction was stirred at rt overnight and concentrated to dryness to giveI-42.

Preparation of Intermediate I-43 and I-44

Tert-Butyl ((1r,4r)-4-(1H-tetrazol-5-yl)cyclohexyl)carbamate (I-43B)

To a solution of tert-butyl ((1r,4r)-4-cyanocyclohexyl)carbamate (I-43A,1000 mg, 4.46 mmol) in DMF (15 mL), was added sodium azide (1014 mg,15.6 mmol) and Ammonium chloride (835 mg, 15.6 mmol). The reaction washeated at 120 deg for 48 hr. The reaction was diluted with EtOAc andwashed with LiCl 5% 3×. The organic extracts were dried over sodiumsulfate, filtered, and concentrated to give I-43B ES/MS: 268.0 (M+H⁺).

1H NMR (400 MHz, Chloroform-d) δ 4.42 (s, 1H), 3.48 (s, 1H), 2.42 (tt,J=11.7, 3.5 Hz, 1H), 2.11 (dtt, J=12.2, 7.5, 3.7 Hz, 4H), 1.81-1.55 (m,2H), 1.46 (s, 9H), 1.29-1.04 (m, 2H).

Tert-Butyl ((1r,4r)-4-(1-methyl-1H-tetrazol-5-yl)cyclohexyl)carbamate(I-43C) Tert-Butyl((1R,4r)-4-((R)-2-methyl-5H-2λ⁴-tetrazol-5-yl)cyclohexyl)carbamate(I-43D)

To a solution of tert-butyl((1r,4r)-4-(1H-tetrazol-5-yl)cyclohexyl)carbamate (I-43B, 638 mg, 2.387mmol) in MeOH (15 mL) at 0 deg, was added 2M(Trimethylsilyl)diazomethane solution 2.0 M in hexanes (2500 μl). Thereaction was gradually warmed to room temp and stirred. The reaction wasquenched carefully with AcOH until gas evolution stopped. The solutionwas diluted with EtOAc, washed with sat'd NaHCO₃, dried with sodiumsulfate, and purified by silica gel chromatography (eluent:EtOAc/hexanes) to provide minor product I-43C and major product I-43D

I-43D (Major)

(M+H+) 281.9

1H NMR (400 MHz, Chloroform-d) δ 4.47 (s, 1H), 4.03 (s, 3H), 3.56 (s,1H), 2.78 (tt, J=12.1, 3.7 Hz, 1H), 2.34-2.15 (m, 3H), 2.15-1.98 (m,3H), 1.89 (qd, J=13.2, 3.4 Hz, 3H), 1.47 (s, 11H), 1.30 (qd, J=12.7, 4.3Hz, 3H).

I-43C (Minor)

(M+H+) 281.9

1H NMR (400 MHz, Chloroform-d) δ 4.47 (d, J=8.4 Hz, 1H), 4.31 (s, 3H),3.52 (s, 1H), 2.89 (tt, J=12.2, 3.4 Hz, 1H), 2.30-2.09 (m, 5H),1.78-1.58 (m, 3H), 1.46 (s, 11H), 1.39-1.09 (m, 3H).

(1r,4r)-4-(1-methyl-1H-tetrazol-5-yl)cyclohexan-1-amine hydrochloride(I-43)

To a solution of tert-butyl((1r,4r)-4-(1-methyl-1H-tetrazol-5-yl)cyclohexyl)carbamate (I-43C, 99.4mg, 0.353 mmol) in DCM (5 mL) was added HCl (0.6 mL, 4.0M in dioxane).The reaction was stirred at rt overnight and concentrated to dryness togive I-43.

(1R,4r)-4-((R)-2-methyl-5H-2λ⁴-tetrazol-5-yl)cyclohexan-1-aminehydrochloride (I-44)

To a solution of tert-butyl((1R,4r)-4-((R)-2-methyl-5H-2λ⁴-tetrazol-5-yl)cyclohexyl)carbamate(I-43D, 369.9 mg, 1.315 mmol) in DCM (8 mL) was added HCl (2.2 mL, 4.0Min dioxane). The reaction was stirred at rt overnight and concentratedto dryness to give I-44.

Preparation of Intermediate I-45

Intermediate I-45 was prepared in the manner described for I-2substituting1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolewith1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

Preparation of Intermediate I-46

Benzyl((1r,4r)-4-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)cyclohexyl)carbamate

To a solution of N-CBZ-trans-1,4-cyclohexanediamine (200 mg, 0.81 mmol),1H-Imidazole-1-sulfonyl azide hydrogen sulfate (328 mg, 1.2 mmol), andpotassium carbonate (334 mg, 2.4 mmol) in MeOH (5.4 mL) was added coppersulfate pentahydrate (24.1 mg, 0.10 mmol). The reaction mixture wasstirred at room temperature for 16 hours. After 16 hours, to thesolution was added acetic acid (0.24 mL, 4.0 mmol), copper powder (25.5mg, 0.40 mmol), copper sulfate (10% w/v in water, 1.6 mL), MeTHF (0.8mL), and cyclopropylacetylene (26.5 mg, 0.4 mmol). The reaction mixturewas stirred at room temperature for 3 hours, then diluted with water andMeTHF. The organic layer was isolated, filtered, concentrated in vacuoand purified by silica gel column chromatography (eluent: EtOAc/Hex) toprovide benzyl((1r,4r)-4-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)cyclohexyl)carbamate.

ES/MS: 340.4 [M+H⁺].

(1r,4r)-4-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)cyclohexan-1-amine (I-46)

To a solution of benzyl((1r,4r)-4-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)cyclohexyl)carbamate(93.4 mg, 0.27 mmol) in EtOH (4.0 mL) was added Pd/C (29.2 mg, 0.027mmol). The reaction flask was subjected to vacuum and backflushed withhydrogen gas three times. The reaction was maintained under a hydrogenatmosphere for 3 hours. The reaction mixture was filtered through a padof Celite and concentrated to provide I-46 which was used withoutpurification.

ES/MS: 207.0 [M+H⁺].

Preparation of Intermediates I-47 and I-48

Intermediates I-47 and I-48 was prepared in the manner described forI-46 substituting cyclopropylacetylene with 3-ethynyloxetane andpropiolamide respectively.

Preparation of Intermediate I-49

Benzyl((1r,4r)-4-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)cyclohexyl)carbamate

To a solution of benzyl((1r,4r)-4-(4-formyl-1H-1,2,3-triazol-1-yl)cyclohexyl)carbamate(obtained as described in Preparation of Intermediate I-46 substitutingpropynal for cyclopropylacetylene) (200 mg, 0.61 mmol) in DCM (3.0 mL)was added DAST (169 μL, 1.28 mmol). The reaction mixture was stirred atroom temperature for one hour, then quenched by the dropwise addition ofsaturated aqueous sodium bicarbonate. The organic layer was isolated,concentrated in vacuo and purified by silica gel column chromatography(eluent: EtOAc/Hex) to provide benzyl ((1r,4r)-4-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)cyclohexyl)carbamate.

ES/MS: 351.2 [M+H⁺].

(1r,4r)-4-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)cyclohexan-1-amine(I-49)

To a solution of benzyl((1r,4r)-4-(4-(difluoromethyl)-1H-1,2,3-triazol-1-yl)cyclohexyl)carbamate(105 mg, 0.30 mmol) in EtOH (5.0 mL) was added Pd/C (15.8 mg, 0.015mmol). The reaction flask was subjected to vacuum and backflushed withhydrogen gas three times. The reaction was maintained under a hydrogenatmosphere for 3 hours. The reaction mixture was filtered through a padof Celite and concentrated to provide I-49 which was used withoutpurification.

ES/MS: 216.2 [M+H⁺].

Preparation of Intermediate I-50

Tert-Butyl (4-(1-tosyl-1H-pyrazol-3-yl)cyclohex-3-en-1-yl)carbamate

A suspension of tert-butyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)carbamate(450 mg, 1.392 mmol), 3-bromo-1-tosyl-1H-pyrazole (500 mg, 1.660 mmol),Palladium acetate (16 mg, 0.071 mmol), Butyldi-1-adamantylphosphine min.95% (53 mg, 0.148 mmol), and Potassium carbonate (385 mg, 12.786 mmol)in DME (8 mL) and water (4 mL) was degassed for 10 min with argon, thenheated at 80 deg o/n. The reaction was diluted with EtOAc, washed withbrine, and dried over sodium sulfate. Chromatographed (eluent:EtOAc/hexanes) gave product tert-butyl(4-(1-tosyl-1H-pyrazol-3-yl)cyclohex-3-en-1-yl)carbamate.

1H NMR (400 MHz, Chloroform-d) δ 8.01 (d, J=2.8 Hz, 1H), 7.96-7.86 (m,2H), 7.52 (d, J=2.4 Hz, 1H), 7.33 (d, J=8.2 Hz, 2H), 6.45 (d, J=2.8 Hz,1H), 6.38 (d, J=2.4 Hz, 1H), 6.29-6.19 (m, 1H), 4.58 (s, 1H), 3.86 (s,1H), 2.73-2.44 (m, 3H), 2.44 (s, 3H), 2.18-2.02 (m, 1H), 2.02-1.83 (m,1H), 1.78-1.57 (m, 1H), 1.46 (s, 9H).

ES/MS: 417.2 (M+H⁺).

Tert-Butyl (4-(1H-pyrazol-3-yl)cyclohex-3-en-1-yl)carbamate

A suspension of tert-butyl(4-(1-tosyl-1H-pyrazol-3-yl)cyclohex-3-en-1-yl)carbamate (0.345 g, 0.826mmol) and Sodium Hydroxide (184 mg, 4.6 mmol) in MeOH (5 mL) was stirredat rt for 4 hr. The reaction was concentrated to dryness, then dilutedwith EtOAc, neutralized with 1N HCl (5 mL), and dried over sodiumsulfate to give product tert-butyl(4-(1H-pyrazol-3-yl)cyclohex-3-en-1-yl)carbamate.

1H NMR (400 MHz, Chloroform-d) δ 9.19 (s, 2H), 7.57 (d, J=2.3 Hz, 1H),6.37 (d, J=2.4 Hz, 1H), 6.31-6.12 (m, 1H), 4.65 (s, 0H), 3.92-3.66 (m,1H), 2.85-2.44 (m, 2H), 2.18-1.88 (m, 2H), 1.85-1.53 (m, 1H), 1.47 (s,6H), 1.35-1.11 (m, 1H), 0.97-0.74 (m, 0H).

ES/MS: 263.8 (M+H⁺).

(1r,4r)-4-(2-(difluoromethyl)-2H-tetrazol-5-yl)cyclohexan-1-amine (I-50)

A solution of tert-butyl(4-(1H-pyrazol-3-yl)cyclohex-3-en-1-yl)carbamate (0.315 g, 1.2 mmol) inEtOH (25 mL) was degassed with argon and vacuum. Pd/C (10%, 64 mg, 0.06mmol) was added and the mixture was stirred with a balloon of H₂overnight. The reaction was filtered over a Celite plug, rinsed withEtOAc and the filtrate was concentrated to give 183 mg of tert-butyl(4-(1H-pyrazol-3-yl)cyclohexyl)carbamate.

ES/MS: 266 (M+H⁺).

To a solution of tert-butyl (4-(1H-pyrazol-3-yl)cyclohexyl)carbamate(183 mg, 0.690 mmol) in DCM (8 mL) was added HCl (4.0M in dioxane, 1.1mL, 4.4 mmol) and the resulting solution stirred at room temperatureovernight. Upon completion, the reaction mixture was concentrated todryness to give 4-(1H-pyrazol-3-yl)cyclohexan-1-amine hydrochloride(I-50) which was used without further purification.

Preparation of Intermediate I-51

(1r,4r)-4-(dibenzylamino)cyclohexane-1-carbonitrile

To a solution of 4-aminocyclohexanecarbonitrile hydrochloride (977 mg,6.08 mmol) and potassium carbonate (3362.09 mg, 24.33 mmol) in CH3CN (15mL), was added benzyl bromide (1800 μl, 15.13 mmol). The reaction washeated at 80 deg o/n. The reaction mixture was filtered and the filtratewas diluted with EtOAc and brine. The organic extract was dried oversodium sulfate and chromatographed (eluent EtOAc/hexanes to give product(1r,4r)-N,N-dibenzyl-4-(1H-tetrazol-5-yl)cyclohexan-1-amine.

1H NMR (400 MHz, Chloroform-d) δ 7.49-7.33 (m, 9H), 7.30 (dq, J=5.4, 1.9Hz, 2H), 3.67 (d, J=3.4 Hz, 4H), 2.59 (tt, J=11.5, 3.5 Hz, 1H),2.42-2.27 (m, 1H), 2.20 (dt, J=12.6, 2.9 Hz, 3H), 2.14-1.98 (m, 3H),1.47 (dqd, J=48.7, 13.0, 3.3 Hz, 6H).

(M+H⁺) 305.3

(1r,4r)-N,N-dibenzyl-4-(1H-tetrazol-5-yl)cyclohexan-1-amine

To a solution of tert-butyl N-(4-cyanocyclohexyl)carbamate (1431 mg,4.70 mmol) in DMF (15 mL), was added sodium azide (1080 mg, 16.46 mmol)and ammonium chloride (880 mg, 16.45 mmol). The reaction was heated at120 deg for 48 hr. The reaction mixture was diluted with EtOAc andwashed with LiCl 5% solution 3×. The organic extract was dried oversodium sulfate and chromatographed (eluent EtOAc/hexanes) to give atautomeric mixture of products(1r,4r)-N,N-dibenzyl-4-(1H-tetrazol-5-yl)cyclohexan-1-amine and(1r,4r)-N,N-dibenzyl-4-(2H-tetrazol-5-yl)cyclohexan-1-amine.

1H NMR (400 MHz, Chloroform-d) δ 7.44-7.33 (m, 4H), 7.33-7.26 (m, 5H),7.26-7.18 (m, 2H), 7.00 (s, 3H), 3.76 (s, 4H), 3.00 (s, 2H), 2.91 (s,1H), 2.77 (s, 1H), 2.16 (dd, J=53.1, 7.7 Hz, 5H), 1.71-1.49 (m, 4H).

(M+H⁺) 348.2

(1r,4r)-N,N-dibenzyl-4-(2-(difluoromethyl)-2H-tetrazol-5-yl)cyclohexan-1-amine

In a 40 mL reaction vial containing a tautomeric mixture of(1r,4r)-N,N-dibenzyl-4-(1H-tetrazol-5-yl)cyclohexan-1-amine and(1r,4r)-N,N-dibenzyl-4-(2H-tetrazol-5-yl)cyclohexan-1-amine and cesiumcarbonate (1077 mg, 3.31 mmol), was added difluoroiodomethane (8.0 ml, 4mmol, 10% wt. in THF). The suspension was heated at 40 deg o/n. Thereaction was diluted with EtOAc and washed with brine. The organicextract was dried over sodium sulfate and chromatographed (eluentEtOAc/hexanes) to give a major product(1r,4r)-N,N-dibenzyl-4-(2-(difluoromethyl)-2H-tetrazol-5-yl)cyclohexan-1-amineand minor product(1r,4r)-N,N-dibenzyl-4-(1-(difluoromethyl)-1H-tetrazol-5-yl)cyclohexan-1-amine.

1H NMR (400 MHz, Chloroform-d) δ 7.58 (d, J=57.9 Hz, 1H), 7.43-7.37 (m,4H), 7.36-7.30 (m, 4H), 7.28-7.22 (m, 2H), 3.69 (s, 4H), 3.05 (ddd,J=12.5, 9.3, 3.5 Hz, 1H), 2.81-2.61 (m, 1H), 2.11 (dt, J=13.1, 2.9 Hz,4H), 1.77 (td, J=14.0, 11.0 Hz, 2H), 1.64-1.49 (m, 2H).

(M+H⁺) 398.4

(1r,4r)-4-(2-(difluoromethyl)-2H-tetrazol-5-yl)cyclohexan-1-amine (I-51)

A suspension of(1r,4r)-N,N-dibenzyl-4-(2-(difluoromethyl)-2H-tetrazol-5-yl)cyclohexan-1-amine(392.5 mg, 0.987 mmol) in EtOH (20 mL) was degassed with argon. Pd/C(10%, 52 mg, 0.049 mmol) was added and purged once more with argon andstirred with a balloon of hydrogen at rt overnight. The suspension wasfiltered through a fritted funnel with Celite and concentrated to giveproduct (1r,4r)-4-(2-(difluoromethyl)-2H-tetrazol-5-yl)cyclohexan-1-amine (I-51),which was used without further purification.

1H NMR (400 MHz, Chloroform-d) δ 7.67 (t, J=58.0 Hz, 1H), 3.07 (tt,J=12.2, 3.4 Hz, 1H), 2.85 (tt, J=11.3, 3.7 Hz, 1H), 2.07 (dtd, J=12.7,7.1, 6.1, 3.2 Hz, 4H), 1.89 (qd, J=14.2, 13.4, 3.5 Hz, 2H), 1.53 (s,2H), 1.37-1.21 (m, 2H).

(M+H⁺) 218.0

Example Procedures and Compound Examples Procedure 1: Example 426-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(((1r,4R)-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)cyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(Example 42)

(R)-6-bromo-4-chloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide

To a solution of 6-bromo-4-chloronicotinic acid (3 g, 12.69 mmol) in DMF(42 mL) was added HATU (6.27 g, 16.49 mmol),(R)-4-amino-3-fluoro-2-methylbutan-2-ol hydrochloride (2.4 g, 15.23mmol), and N,N-Diisopropylethylamine (5.62 ml, 32.26 mmol). Theresulting solution was stirred at room temperature overnight andsubsequently diluted with ethyl acetate. The organic solution was washedwith saturated aqueous lithium chloride (3 times), then dried overNa₂SO₄, and then concentrated. The residue was purified by silica gelchromatography (eluent: EtOAc/hexanes) to provide(R)-6-bromo-4-chloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide.

ES/MS: 341.1 (M+H⁺).

6-chloro-4-(((1r,4R)-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)cyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide

(R)-4,6-dichloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (0.23g, 0.78 mmol) and(1r,4r)-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)cyclohexan-1-aminehydrochloride I-24 (0.26 g, 1.00 mmol) were added to a microwave vialfollowed by NMP (4 mL) and diisopropylethylamine (0.68 mL, 3.90 mmol).The resulting solution was heated to 160° C. in a microwave reactor for45 min. The reaction mixture was then poured into water (8 mL) andextracted with EtOAc (2×30 mL). The organic layers were then combined,dried over MgSO₄, filtered and concentrated with the resulting cruderesidue then purified via silica gel chromatography (eluent:EtOAc/hexanes/MeOH) to give the desired product. Note: In someinstances, heating to 160° C. in a microwave reactor for up to 8 hoursis necessary.

ES/MS: 477.0 (M+H⁺).

6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(((1r,4R)-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)cyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(Example 42)

6-chloro-4-(((1r,4R)-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)cyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(0.21 g, 0.44 mmol) and7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(0.17 g, 0.62 mmol) were added to a microwave vial followed by DME (3.5mL), XPhos Pd G3 (37 mg, 0.044 mmol) and K₃PO₄ (0.5M in water, 1.3 mL,0.66 mmol). The resulting mixture was purged with argon for 2 minutes,sealed and heated to 120° C. in a microwave reactor for 10 min. Thereaction mixture was filtered and purified by RP-HPLC (eluent:water/MeCN*0.1% TFA). The product fractions were combined andlyophilized to give the final product as a TFA salt.

ES/MS: 583.4 (M+H⁺).

1H NMR (400 MHz, Methanol-d4) δ 8.75 (d, J=2.2 Hz, 1H), 8.67 (d, J=2.2Hz, 1H), 8.58 (s, 1H), 8.03 (d, J=5.0 Hz, 1H), 7.91 (s, 1H), 7.21 (d,J=5.1 Hz, 1H), 7.14 (t, J=51.6 Hz, 1H), 4.42 (ddd, J=49.0, 9.4, 2.1 Hz,1H), 4.12-3.79 (m, 2H), 3.63-3.41 (m, 1H), 3.26-3.12 (m, 1H), 2.47-2.20(m, 4H), 2.04-1.84 (m, 2H), 1.76-1.60 (m, 2H), 1.29 (d, J=1.6 Hz, 6H).

Procedure 2: Example 36-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(((1r,4R)-4-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(Example 3)

6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(((1r,4R)-4-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(Example 3)

(R)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-((4-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclohexyl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(obtained as described in Procedure 1 substituting(1r,4r)-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)cyclohexan-1-aminehydrochloride with4-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclohexan-1-amine hydrochloride(I-2)) was separated by reverse phase high pressure liquidchromatography (SFC IA, eluent: SFC/EtOH) to provide the final compound.

ES/MS: 581.2 [M+H⁺].

1H NMR (400 MHz, Methanol-d4) δ 8.61-8.57 (m, 2H), 8.55 (d, J=2.2 Hz,1H), 8.24 (s, 1H), 7.96 (s, 1H), 7.83 (d, J=4.8 Hz, 1H), 7.72 (s, 1H),7.43 (t, J=59.9 Hz, 1H), 7.11 (d, J=4.9 Hz, 1H), 4.45 (ddd, J=49.0, 9.1,2.2 Hz, 1H), 3.90 (ddd, J=35.6, 14.5, 2.3 Hz, 1H), 3.70-3.58 (m, 1H),3.57-3.41 (m, 1H), 2.70 (t, J=11.8 Hz, 1H), 2.36 (d, J=12.4 Hz, 2H),2.18 (d, J=13.2 Hz, 2H), 1.69 (q, J=11.5 Hz, 2H), 1.61-1.44 (m, 2H),1.32 (d, J=1.7 Hz, 6H).

Procedure 3: Example 86-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(((1r,4R)-4-(1-(difluoromethyl)-1H-pyrazol-3-yl)cyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(Example 8)

6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(((1r,4R)-4-(1-(difluoromethyl)-1H-pyrazol-3-yl)cyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(Example 8)

(R)-6-chloro-4-((4-(1-(difluoromethyl)-1H-pyrazol-3-yl)cyclohexyl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(obtained in the manner described in Procedure 1 substituting(1r,4r)-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)cyclohexan-1-aminehydrochloride I-24 with4-(1-(difluoromethyl)-1H-pyrazol-3-yl)cyclohexan-1-amine hydrochlorideI-13) was purified by chiral SFC on an SFC-ID column with SFC 70%EtOH-TFA as co-solvent to deliver pure6-chloro-4-(((1r,4R)-4-(1-(difluoromethyl)-1H-pyrazol-3-yl)cyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamidewhich was elaborated to the final compound6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(((1r,4R)-4-(1-(difluoromethyl)-1H-pyrazol-3-yl)cyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamideExample 8 according to the same procedure as described for step 2 ofProcedure 1.

ES/MS: 581.4 (M+H⁺).

1H NMR (400 MHz, Methanol-d4) δ 8.60 (s, 1H), 8.58 (d, J=2.3 Hz, 1H),8.54 (d, J=2.2 Hz, 1H), 8.25 (s, 1H), 7.96 (d, J=2.6 Hz, 1H), 7.83 (d,J=4.9 Hz, 1H), 7.42 (t, J=59.9 Hz, 1H), 7.11 (d, J=4.9 Hz, 1H), 6.48 (d,J=2.7 Hz, 1H), 4.57-4.30 (m, 0H), 3.91 (d, J=52.2 Hz, 0H), 3.37 (s, 3H),2.83 (s, 1H), 2.37 (d, J=12.3 Hz, 2H), 2.19 (d, J=13.4 Hz, 2H), 1.79 (d,J=13.4 Hz, 1H), 1.53 (d, J=12.2 Hz, 1H), 1.32 (d, J=1.7 Hz, 6H).

Procedure 4: Example 76-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((1r,4R)-4-(1-methyl-1H-pyrazol-4-yl)cyclohexyl)amino)nicotinamide(Example 7)

6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((1r,4R)-4-(1-methyl-1H-pyrazol-4-yl)cyclohexyl)amino)nicotinamide(Example 7)

(R)-6-chloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((4-(1-methyl-1H-pyrazol-4-yl)cyclohexyl)amino)nicotinamide(synthesized according to step 1 of Procedure 1) was purified by silicagel chromatography (eluent EtOAc/hexanes) to deliver pure6-chloro-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((1r,4R)-4-(1-methyl-1H-pyrazol-4-yl)cyclohexyl)amino)nicotinamide whichwas elaborated to the final compound6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((1r,4R)-4-(1-methyl-1H-pyrazol-4-yl)cyclohexyl)amino)nicotinamideExample 7 according to the same procedure as described for step 2 ofProcedure 1.

ES/MS: 545.3 (M+H⁺).

1H NMR (400 MHz, Methanol-d4) δ 9.01 (d, J=5.9 Hz, 0H), 8.77 (d, J=2.2Hz, 1H), 8.69 (d, J=2.1 Hz, 1H), 8.59 (s, 1H), 8.04 (d, J=5.1 Hz, 1H),7.92 (s, 1H), 7.48 (s, 1H), 7.41 (s, 1H), 7.23 (d, J=5.1 Hz, 1H), 4.45(ddd, J=49.0, 9.4, 2.2 Hz, 1H), 4.12-3.88 (m, 1H), 3.87 (s, 3H),3.69-3.41 (m, 1H), 2.72-2.53 (m, 0H), 2.28 (d, J=10.9 Hz, 2H), 2.15 (d,J=11.9 Hz, 2H), 1.65 (h, J=12.0 Hz, 4H), 1.31 (d, J=1.7 Hz, 6H).

Procedure 5: Examples 23 and 286-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(((1r,4R)-4-(3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(Example 23) and6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(((1r,4R)-4-(5-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(Example 28)

Ethyl6-chloro-4-(((1s,4s)-4-((methylsulfonyl)oxy)cyclohexyl)amino)nicotinate

A solution of ethyl 4,6-dichloronicotinate (11.5 g, 52.3 mmol) and(1s,4s)-4-aminocyclohexan-1-ol (15.9 g, 105 mmol) in acetonitrile (120mL) was heated at 80° C. for 16 h then concentrated directly and usedwithout further purification. The crude ethyl6-chloro-4-(((1s,4s)-4-hydroxycyclohexyl)amino)nicotinate (14.0 g, 46.9mmol) was then dissolved in DCM (250 mL) and triethylamine (16.3 mL, 117mmol) after which methanesulfonyl chloride (7.25 mL, 93.7 mmol) wasadded and the resulting solution stirred for 5 h at room temperature.Upon completion the reaction mixture was concentrated directly and thecrude residue purified by silica gel chromatography (eluent:EtOAc/hexanes) to give ethyl6-chloro-4-(((1s,4s)-4-((methylsulfonyl)oxy)cyclohexyl)amino)nicotinate.

ES/MS: 377.5 (M+H⁺).

Ethyl6-chloro-4-(((1r,4r)-4-(3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)amino)nicotinateand ethyl6-chloro-4-(((1r,4r)-4-(5-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)amino)nicotinate

To a solution of 3-(difluoromethyl)-1H-pyrazole (0.17 g, 1.46 mmol) inDMF (4 mL) was added NaH (60% dispersion in mineral oil, 56 mg, 1.39mmol) and the resulting suspension stirred for 10 minutes at roomtemperature. give ethyl 6-chloro-4-(((1s,4s)-4-((methylsulfonyl)oxy)cyclohexyl)amino)nicotinate (0.50 g, 1.33mmol) was then added and the resulting mixture heated to 100° C. for 2h. Upon completion the reaction mixture was cooled to room temperature,diluted with EtOAc (30 mL), washed with brine (5 mL), dried over MgSO₄,filtered and concentrated to give a mixture of ethyl6-chloro-4-(((1r,4r)-4-(3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)amino)nicotinateand ethyl 6-chloro-4-(((1r,4r)-4-(5-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)amino)nicotinatewhich was used without further purification.

6-chloro-4-(((1r,4R)-4-(3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamideand6-chloro-4-(((1r,4R)-4-(5-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide

A mixture of ethyl6-chloro-4-(((1r,4r)-4-(3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)amino)nicotinateand ethyl6-chloro-4-(((1r,4r)-4-(5-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)amino)nicotinate(0.10 g, 0.25 mmol) was dissolved in MeOH (1 mL) and THF (1 mL) afterwhich LiOH (2M aq., 1 mL, 2 mmol) was added and the resulting solutionstirred at room temperature for 2 h. Upon completion the crude reactionmixture was purified by RP-HPLC (eluent: water/MeCN*0.1% TFA). Themixture of6-chloro-4-(((1r,4r)-4-(3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)amino)nicotinicacid and6-chloro-4-(((1r,4r)-4-(5-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)amino)nicotinicacid (82 mg, 0.22 mmol) was then dissolved in NMP (0.5 mL) and this wasfollowed by the sequential addition of HATU (91 mg, 0.24 mmol) andtriethylamine (0.2 mL). After 20 minutes stirring at room temperature(R)-4-amino-3-fluoro-2-methylbutan-2-ol hydrochloride (70 mg, 0.44 mmol)was added and the resulting reaction mixture stirred for 30 minutes.Upon completion the reaction mixture was diluted with EtOAc (20 mL),washed with saturated aqueous NaHCO₃ (5 mL) then brine (5 mL), dried andconcentrated to give a mixture of6-chloro-4-(((1r,4R)-4-(3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamideand6-chloro-4-(((1r,4R)-4-(5-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamidewhich was used without further purification.

ES/MS: 474.2 (M+H⁺).

6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(((1r,4R)-4-(3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(Example 23) and6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(((1r,4R)-4-(5-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(Example 28)

6-chloro-4-(((1r,4R)-4-(3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamideand 6-chloro-4-(((1r,4R)-4-(5-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(0.10 g, 0.21 mmol) and7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(0.11 g, 0.42 mmol) were added to a microwave vial followed by DME (1mL), XPhos Pd G3 (18 mg, 0.021 mmol) and K₃PO₄ (2M in water, 0.21 mL,0.42 mmol). The resulting mixture was purged with argon for 2 minutes,sealed and heated to 120° C. in a microwave reactor for 20 min. Thereaction mixture was filtered and purified by RP-HPLC (eluent:water/MeCN*0.1% TFA). The mixture of6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(((1r,4R)-4-(3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamideand6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(((1r,4R)-4-(5-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamidewas separated by chiral SFC on an SFC IE column with SFC 80% EtOH-TFA asco-solvent.

6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(((1r,4R)-4-(3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(Example 23)

ES/MS: 581.6 (M+H⁺).

1H NMR (400 MHz, Methanol-d4) δ 8.68 (d, J=2.1 Hz, 1H), 8.59 (d, J=1.7Hz, 1H), 8.05 (dd, J=5.1, 1.7 Hz, 1H), 7.94 (d, J=1.7 Hz, 1H), 7.76 (d,J=2.4 Hz, 1H), 7.21 (dd, J=5.2, 1.6 Hz, 1H), 6.73 (td, J=55.1, 1.7 Hz,1H), 6.49 (d, J=2.7 Hz, 1H), 4.58-4.26 (m, 2H), 4.08-3.80 (m, 2H),3.61-3.42 (m, 1H), 2.39-2.30 (m, 2H), 2.25 (d, J=11.0 Hz, 2H), 2.19-2.03(m, 2H), 1.71 (qd, J=12.9, 3.5 Hz, 2H), 1.29 (d, J=1.7 Hz, 6H).

6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(((1r,4R)-4-(5-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(Example 28)

ES/MS: 581.3 (M+H⁺).

1H NMR (400 MHz, Methanol-d4) δ 8.75 (d, J=2.3 Hz, 1H), 8.69 (d, J=2.3Hz, 1H), 8.58 (s, 1H), 8.06 (d, J=5.0 Hz, 1H), 7.98 (s, 1H), 7.58 (d,J=1.8 Hz, 1H), 7.33-6.89 (m, 2H), 6.63-6.52 (m, 1H), 4.57-4.30 (m, 2H),4.07-3.82 (m, 2H), 3.65-3.43 (m, 1H), 2.47-2.21 (m, 4H), 2.13 (d, J=13.0Hz, 2H), 1.71 (q, J=12.4 Hz, 2H), 1.29 (d, J=1.7 Hz, 6H).

Procedure 6: Examples 1 and 24-(((1r,4R)-4-(1H-pyrazol-4-yl)cyclohexyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(Example 1) and4-(((1s,4S)-4-(1H-pyrazol-4-yl)cyclohexyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(Example 2)

4-(((1r,4R)-4-(1H-pyrazol-4-yl)cyclohexyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(Example 1) and4-(((1s,4S)-4-(1H-pyrazol-4-yl)cyclohexyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(Example 2)

To a solution of6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)cyclohexyl)amino)nicotinamide(obtained as described in Procedure 1 substituting(1r,4r)-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)cyclohexan-1-aminehydrochloride with4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)cyclohexan-1-aminehydrochloride (I-44)) in DCM (5 mL), was added TFA (0.2 mL). Thereaction was stirred at room temperature overnight. The reaction wasconcentrated and purified by RP-HPLC (eluent: water/MeCN*0.1% TFA). Theproduct fractions were combined, lyophilized, and further separated bychiral RP-HPLC (SFC ODH, eluent: SFC/iPrOH) to provide the finalcompounds.

Example 1

ES/MS: 531.3 [M+H⁺].

1H NMR (400 MHz, Methanol-d4) δ 8.77 (d, J=2.1 Hz, 1H), 8.69 (d, J=2.2Hz, 1H), 8.60 (s, 1H), 8.05 (d, J=5.1 Hz, 1H), 7.93 (s, 1H), 7.57 (s,2H), 7.23 (d, J=5.0 Hz, 1H), 4.45 (ddd, J=49.1, 9.4, 2.1 Hz, 1H),4.10-3.85 (m, 2H), 3.52 (ddd, J=16.0, 14.5, 9.4 Hz, 1H), 2.71 (t, J=11.5Hz, 1H), 2.38-2.23 (m, 2H), 2.24-2.05 (m, 2H), 1.89-1.52 (m, 4H), 1.32(d, J=1.7 Hz, 6H), 0.97-0.78 (m, 1H).

19F NMR (376 MHz, Methanol-d4) δ −77.56, −195.84 (ddd, J=50.7, 36.4,16.0 Hz).

Example 2

ES/MS: 531.3 [M+H⁺].

1H NMR (400 MHz, Methanol-d4) δ 8.78 (d, J=2.2 Hz, 1H), 8.69 (d, J=2.2Hz, 1H), 8.63 (s, 1H), 8.03 (d, J=5.1 Hz, 1H), 7.90 (s, 1H), 7.56 (s,2H), 7.24 (d, J=5.0 Hz, 1H), 4.45 (ddd, J=49.1, 9.4, 2.2 Hz, 1H), 4.26(s, 1H), 3.96 (ddd, J=36.5, 14.5, 2.2 Hz, 1H), 3.56-3.42 (m, 1H), 2.82(t, J=10.5 Hz, 1H), 2.03 (d, J=11.0 Hz, 7H), 1.77 (d, J=11.4 Hz, 2H),1.31 (d, J=1.7 Hz, 6H), 0.97-0.82 (m, 1H).

Procedure 7: Example 68(R)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-((4-(4,4-difluoropiperidin-1-yl)bicyclo[2.2.2]octan-1-yl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(Example 68)

(R)-4-((4-aminobicyclo[2.2.2]octan-1-yl)amino)-6-chloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamidehydrochloride

tert-butyl(R)-(4-((2-chloro-5-((2-fluoro-3-hydroxy-3-methylbutyl)carbamoyl)pyridin-4-yl)amino)bicyclo[2.2.2]octan-1-yl)carbamate(0.35 g, 0.70 mmol) (obtained in the manner described in step 1 ofProcedure 1 substituting(1r,4r)-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)cyclohexan-1-aminehydrochloride I-24 with tert-butyl(4-aminobicyclo[2.2.2]octan-1-yl)carbamate hydrochloride) was dissolvedin HCl solution (4.0M in dioxane, 3 mL, 12 mmol) and stirred for 3 h atroom temperature. Upon completion the reaction mixture was concentratedto dryness to give(R)-4-((4-aminobicyclo[2.2.2]octan-1-yl)amino)-6-chloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamidehydrochloride which was used without further purification.

(R)-6-chloro-4-((4-(4,4-difluoropiperidin-1-yl)bicyclo[2.2.2]octan-1-yl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide

To a solution of 3,3-difluoropentane-1,5-diol (100 mg, 0.71 mmol) andtriethylamine (0.5 mL, 3.5 mmol) in 2 mL of DCM, methanesulfonylchloride (0.17 mL, 2.1 mmol) was added to the solution. It was stirredfor overnight. Diluted with 30 mL of ethylacetate and washed with NaHCO₃and brine. The organic layer was dried and concentrated. Used withoutfurther purification. The crude product and(R)-4-((4-aminobicyclo[2.2.2]octan-1-yl)amino)-6-chloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamidehydrochloride (100 mg, 0.23 mmol) were dissolved in toluene (3 mL),powder of NaHCO₃ (143 mg, 2.3 mmol) was added to the solution. It washeated to 110° C. for 16 hours. Removed the solvent and the cruderesidue purified on HPLC prep (eluent: 10% to 50% of water/MeCN*0.1%TFA) to give(R)-6-chloro-4-((4-(4,4-difluoropiperidin-1-yl)bicyclo[2.2.2]octan-1-yl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide.

ES/MS: 503.5 (M+H⁺).

(R)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-((4-(4,4-difluoropiperidin-1-yl)bicyclo[2.2.2]octan-1-yl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(Example 68)

(R)-6-chloro-4-((4-(4,4-difluoropiperidin-1-yl)bicyclo[2.2.2]octan-1-yl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamidewas converted to the final product(R)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-((4-(4,4-difluoropiperidin-1-yl)bicyclo[2.2.2]octan-1-yl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(Example 68) in the manner described in step 2 of Procedure 1substituting6-chloro-4-(((1r,4R)-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)cyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamidewith(R)-6-chloro-4-((4-(4,4-difluoropiperidin-1-yl)bicyclo[2.2.2]octan-1-yl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide.

ES/MS: 610.4 [M+H⁺].

1H NMR (400 MHz, Methanol-d4) δ 8.76 (s, 2H), 8.60 (s, 1H), 8.33 (s,1H), 7.95 (d, J=5.1 Hz, 1H), 7.22 (d, J=5.0 Hz, 1H), 4.40 (ddd, J=49.1,9.4, 2.1 Hz, 1H), 4.05-3.33 (m, 5H), 2.42 (d, J=12.5 Hz, 4H), 2.33 (dd,J=10.0, 5.0 Hz, 6H), 2.22 (dd, J=9.9, 5.1 Hz, 6H), 1.28 (d, J=1.7 Hz,6H).

Procedure 8: Example 69(R)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((4-(3-oxomorpholino)bicyclo[2.2.2]octan-1-yl)amino)nicotinamide(Example 69

(R)-4-((4-aminobicyclo[2.2.2]octan-1-yl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamidehydrochloride

tert-butyl(R)-(4-((2-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-5-((2-fluoro-3-hydroxy-3-methylbutyl)carbamoyl)pyridin-4-yl)amino)bicyclo[2.2.2]octan-1-yl)carbamate(0.14 g, 0.23 mmol) (obtained in the manner described in Procedure 1substituting(1r,4r)-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)cyclohexan-1-aminehydrochloride I-24 with tert-butyl(4-aminobicyclo[2.2.2]octan-1-yl)carbamate hydrochloride) was dissolvedin HCl solution (4.0M in dioxane, 2 mL, 8 mmol) and stirred for 2 h atroom temperature. Upon completion the reaction mixture was concentratedto dryness to give(R)-4-((4-aminobicyclo[2.2.2]octan-1-yl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamidehydrochloride which was used without further purification.

(R)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((4-(3-oxomorpholino)bicyclo[2.2.2]octan-1-yl)amino)nicotinamide(Example 69)

To a suspension of(R)-4-((4-aminobicyclo[2.2.2]octan-1-yl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamidehydrochloride (80 mg, 0.15 mmol) and diisopropylethylamine (0.13 mL,0.74 mmol) in 3 mL of acetonitrile and 1 mL of DMF,2-(2-chloroethoxy)acetyl chloride (46.4 mg, 0.3 mmol) was added to thesolution. Then it was stirred for 1 hour, diluted with 30 mL of ethylacetate and washed with 10 mL of sodium bicarbonate solution and 10 mLof brine. The organic was concentrated. The crude product was dissolvedin THF, 1N of potassium tert-butoxide (0.58 mL, 0.58 mmol) was added tothe solution. It was stirred for 10 minutes. Acidified by 1 N HCl andremoved the solvent. The mixture was purified by HPLC prep (eluent: 10%to 50% of water/MeCN*0.1% TFA) to give(R)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((4-(3-oxomorpholino)bicyclo[2.2.2]octan-1-yl)amino)nicotinamide(Example 69).

ES/MS: 590.7 (M+H⁺).

1H NMR (400 MHz, Methanol-d4) δ 8.76 (t, J=1.5 Hz, 2H), 8.54 (s, 1H),8.41 (s, 1H), 7.92 (d, J=5.1 Hz, 1H), 7.22 (d, J=5.1 Hz, 1H), 4.40 (ddd,J=49.0, 9.4, 2.1 Hz, 1H), 4.05 (s, 2H), 4.00-3.87 (m, 1H), 3.83 (dd,J=6.0, 4.1 Hz, 2H), 3.57-3.42 (m, 3H), 2.40 (dd, J=10.3, 5.3 Hz, 6H),2.24 (dd, J=10.3, 5.4 Hz, 6H), 1.28 (d, J=1.7 Hz, 6H).

Procedure 9: Example 61(R)-4-((4-(1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(Example 61)

(R)-4-((2-chloro-5-((2-fluoro-3-hydroxy-3-methylbutyl)carbamoyl)pyridin-4-yl)amino)bicyclo[2.2.2]octane-1-carboxylicAcid

methyl(R)-4-((2-chloro-5-((2-fluoro-3-hydroxy-3-methylbutyl)carbamoyl)pyridin-4-yl)amino)bicyclo[2.2.2]octane-1-carboxylate(0.80 g, 1.81 mmol) (obtained in the manner described in Procedure 1substituting(1r,4r)-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)cyclohexan-1-aminehydrochloride I-24 with methyl 4-aminobicyclo[2.2.2]octane-1-carboxylatehydrochloride) was dissolved in MeOH (1 mL) and THF (1 mL) after whichLiOH (2M aq., 1.5 mL, 3 mmol) was added and the resulting reactionmixture stirred at room temperature for 2.5 h. Upon completion thereaction mixture was acidified to ˜pH 2-3 using 1N HCl and the solventsremoved under vacuum to give(R)-4-((2-chloro-5-((2-fluoro-3-hydroxy-3-methylbutyl)carbamoyl)pyridin-4-yl)amino)bicyclo[2.2.2]octane-1-carboxylicacid which was used without further purification.

ES/MS: 428.4 (M+H⁺).

(R)-4-((4-(1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)amino)-6-chloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide

Dissolved(R)-4-((2-chloro-5-((2-fluoro-3-hydroxy-3-methylbutyl)carbamoyl)pyridin-4-yl)amino)bicyclo[2.2.2]octane-1-carboxylicacid (100 mg, 0.23 mmol) in 5 mL of DMF,O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (118 mg, 0.28 mmol)) stirred for 30 seconds thenadded diisopropylethylamine (0.06 mL, 0.35 mmol). Formic acid hydrazide(140.3 mg, 2.34 mmol) was added to the mixture after 30 minutes. Thereaction was stirred for 16 hour. Poured into water and extracted withEtOAc. Concentrated residue has significant amount of white solid,filtered washing with DCM which gave 50 mg of crude product. The crudeproduct (50 mg, 0.11 mmol) and Lawesson's reagent (51.6 mg, 0.13 mmol)in 3 mL of dioxane, was heated for 2 h at 80 degree. Cooled it down anddiluted with 30 mL of EtOAc. The organic layer was washed with water andbrine. The mixture was purified by flash column (eluent: EtOAc/hexanes)to give(R)-4-((4-(1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)amino)-6-chloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide.

ES/MS: 468.2 (M+H⁺).

(R)-4-((4-(1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(Example 61)

(R)-4-((4-(1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)amino)-6-chloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamidewas converted to the final product(R)-4-((4-(1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(Example 61) in the manner described in step 2 of Procedure 1substituting6-chloro-4-(((1r,4R)-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)cyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamidewith(R)-4-((4-(1,3,4-thiadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)amino)-6-chloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide.

ES/MS: 575.31 (M+H⁺).

1H NMR (400 MHz, Methanol-d4) δ 9.38 (s, 1H), 8.80-8.73 (m, 2H), 8.56(s, 1H), 8.39 (s, 1H), 7.95 (d, J=5.1 Hz, 1H), 7.22 (d, J=5.1 Hz, 1H),4.58-4.27 (m, 1H), 3.92 (ddd, J=36.6, 14.6, 2.1 Hz, 1H), 3.48 (td,J=15.7, 9.4 Hz, 1H), 2.32 (s, 12H), 1.28 (d, J=1.6 Hz, 6H).

Procedure 10: Example 206-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(((1r,4R)-4-(1-cyclopropyl-1H-1,2,3-triazol-4-yl)cyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(Example 20)

6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(((1r,4R)-4-(1-cyclopropyl-1H-1,2,3-triazol-4-yl)cyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(Example 20)

6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(((1r,4R)-4-ethynylcyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(18 mg, 0.037 mmol) (obtained in the manner described in Procedure 1substituting(1r,4r)-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)cyclohexan-1-aminehydrochloride I-24 with (1r,4r)-4-ethynylcyclohexan-1-aminehydrochloride) was dissolved in DMF (0.6 mL) after which copper(I)thiophene-2-carboxylate (2 mg, 0.009 mmol), cyclopropyl azide (6 mg,0.074 mmol) and triethylamine (15 μL, 0.11 mmol) were added and theresulting mixture stirred for 1 h at room temperature. Upon completionthe crude mixture was filtered and purified by HPLC prep (eluent:water/MeCN*0.1% TFA) to give6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(((1r,4R)-4-(1-cyclopropyl-1H-1,2,3-triazol-4-yl)cyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(Example 20).

ES/MS: 572.3 (M+H⁺).

1H NMR (400 MHz, Methanol-d4) δ 8.78 (d, J=2.2 Hz, 1H), 8.71 (d, J=2.2Hz, 1H), 8.59 (s, 1H), 8.05 (d, J=5.1 Hz, 1H), 7.97 (s, 1H), 7.85 (s,1H), 7.24 (d, J=5.1 Hz, 1H), 4.45 (dd, J=49.1, 7.5 Hz, 1H), 4.07-3.78(m, 2H), 3.61-3.42 (m, 1H), 2.93-2.79 (m, 1H), 2.26 (dd, J=39.3, 12.9Hz, 4H), 1.73 (dd, J=56.0, 12.8 Hz, 4H), 1.37-1.27 (m, 6H), 1.27-1.14(m, 4H).

Procedure 11: Example 196-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((1r,4R)-4-(1-methyl-1H-1,2,3-triazol-4-yl)cyclohexyl)amino)nicotinamide

6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((1r,4R)-4-(1-methyl-1H-1,2,3-triazol-4-yl)cyclohexyl)amino)nicotinamide(Example 19)

Sodium azide (16 mg, 0.25 mmol), methyl iodide (12 uL, 0.18 mmol), andDMF (0.5 mL) were combined in a vial and stirred at 50° C. for 1 h.6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(((1r,4R)-4-ethynylcyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(15 mg, 0.031 mmol) (obtained in the manner described in Procedure 1substituting(1r,4r)-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)cyclohexan-1-aminehydrochloride I-24 with (1r,4r)-4-ethynylcyclohexan-1-aminehydrochloride) and copper(I) thiophene-2-carboxylate (1 mg, 0.0077 mmol)were added and the resulting mixture stirred for 4 h at 50° C.Triethylamine (13 μL, 0.092 mmol) was then added and the reactionmixture stirred for 1 h at room temperature. Upon completion the crudemixture was filtered and purified by HPLC prep (eluent: water/MeCN*0.1%TFA) to give6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((1r,4R)-4-(1-methyl-1H-1,2,3-triazol-4-yl)cyclohexyl)amino)nicotinamide(Example 19).

ES/MS: 546.3 (M+H⁺).

1H NMR (400 MHz, Methanol-d4) δ 8.77 (d, J=2.2 Hz, 1H), 8.70 (d, J=2.2Hz, 1H), 8.59 (s, 1H), 8.04 (d, J=5.0 Hz, 1H), 7.96 (s, 1H), 7.77 (s,1H), 7.23 (d, J=5.1 Hz, 1H), 4.45 (ddd, J=49.2, 9.4, 2.1 Hz, 1H), 4.10(s, 3H), 4.02-3.86 (m, 1H), 3.55-3.44 (m, 2H), 2.88 (d, J=3.5 Hz, 1H),2.26 (dd, J=36.9, 12.9 Hz, 4H), 1.90-1.52 (m, 4H), 1.35-1.25 (m, 6H).

Procedure 12: Example 186-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(((1r,4R)-4-(1-(difluoromethyl)-1H-1,2,3-triazol-4-yl)cyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide

6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(((1r,4R)-4-(1-(difluoromethyl)-1H-1,2,3-triazol-4-yl)cyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(Example 18)

Sodium azide (6 mg, 0.10 mmol), difluoromethyl iodide (10% in THF, 16mg, 0.09 mmol), and DMF (0.5 mL) were combined in a vial and stirred at50° C. for 1 h.6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(((1r,4R)-4-ethynylcyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(15 mg, 0.031 mmol) (obtained in the manner described in Procedure 1substituting(1r,4r)-4-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)cyclohexan-1-aminehydrochloride I-24 with (1r,4r)-4-ethynylcyclohexan-1-aminehydrochloride), copper(I) thiophene-2-carboxylate (2 mg, 0.0092 mmol),copper(I) iodide (3 mg, 0.015 mmol), sodium ascorbate (3 mg, 0.018 mmol)and triethylamine (26 μL, 0.18 mmol) was then added and the reactionmixture stirred for 1 h at room temperature. Upon completion the crudemixture was filtered and purified by HPLC prep (eluent: water/MeCN*0.1%TFA) to give 6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(((1r,4R)-4-(1-(difluoromethyl)-1H-1,2,3-triazol-4-yl)cyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(Example 18).

ES/MS: 582.2 (M+H⁺).

1H NMR (400 MHz, Methanol-d4) δ 8.77 (d, J=2.2 Hz, 1H), 8.71 (d, J=2.2Hz, 1H), 8.59 (s, 1H), 8.32 (s, 1H), 8.14-7.78 (m, 3H), 7.24 (d, J=5.0Hz, 1H), 4.45 (dd, J=49.1, 8.4 Hz, 1H), 3.98 (dd, J=23.8, 12.3 Hz, 1H),3.57-3.44 (m, 2H), 3.04-2.91 (m, 1H), 2.36-2.24 (m, 4H), 1.76 (dd,J=63.9, 12.5 Hz, 4H), 1.36-1.29 (m, 6H).

Procedure 13: Example 756-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(((1r,4R)-4-(2-(difluoromethyl)-2H-1,2,3-triazol-4-yl)cyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide

trans-N,N-dibenzyl-4-ethynylcyclohexan-1-amine

To trans-4-ethynylcyclohexanamine (1 g, 8.12 mmol) in acetonitrile (40mL) was added benzyl bromide (2 mL, 2.03 mmol) and potassium carbonate(4.49 g, 32.5 mmol). The mixture was heated at 60° C. for 48 hrs.Afterward, the mixture was allowed to cool to rt and water (100 mL) wasadded. The mixture was diluted with EtOAc (150 mL), and the layers wereseparated. The aqueous layer was extracted with EtOAc (100 mL). Thecombined organic layers were dried over MgSO4, filtered, andconcentrated under reduced pressure. The crude material was purified bysilica gel chromatography (eluent: EtOAc/hexanes).

ES/MS: 304.362 (M+H⁺)

1H NMR (400 MHz, Chloroform-d) δ 7.40-7.35 (m, 4H), 7.34-7.29 (m, 2H),7.26-7.17 (m, 2H), 3.63 (s, 4H), 2.52 (tt, J=12.8, 4.7 Hz, 1H), 2.16(td, J=12.2, 11.8, 2.7 Hz, 1H), 2.10-1.86 (m, 5H), 1.46-1.21 (m, 4H).

trans-tert-butyl 2-[4-[4-(dibenzylamino)cyclohexyl]triazol-1-yl]acetate

To a solution of trans-N,N-dibenzyl-4-ethynylcyclohexan-1-amine (1.69 g,5.57 mmol) in THF (50 mL), was added copper(I) thiophene-2-carboxylate(319 mg, 1.67 mmol), followed by tert-butyl 2-azidoacetate (1.31 g, 8.35mmol) and stirred at rt in ambient atmosphere for 30 minutes. Uponcompletion, the mixture was poured into sat. aq. NaHCO₃ (50 mL), andextracted with EtOAc (3×75 mL). The combined organic layers were driedover MgSO₄, filtered, and concentrated under reduced pressure. The cruderesidue was carried forward without further purification.

ES/MS: 461.431 (M+H⁺)

trans-N,N-dibenzyl-4-(1H-triazol-4-yl)cyclohexanamine

To a RBF with trans-tert-butyl2-[4-[4-(dibenzylamino)cyclohexyl]triazol-1-yl]acetate (2.57 g, 5.57mmol) was added MeOH (30 mL), followed by NaOH (1M aq, 12.3 mL, 12.3mmol). The mixture was stirred at rt for 30 minutes. To the mixture wasslowly added HCl (1M aq, 12.3 mL, 12.3 mmol), and the mixture was pouredinto water (30 mL) and EtOAc (100 mL). The layers were separated, andthe aqueous layer was extracted with EtOAc (2×50 mL). The combinedorganic layers were dried over MgSO₄, filtered, and concentrated underreduced pressure. The crude material was purified by silica gelchromatography (eluent: EtOAc/hexanes, then MeOH/EtOAc) to afford theproduct.

ES/MS: 347.299 (M+H⁺)

1H NMR (400 MHz, Methanol-d4) δ 7.43-7.35 (m, 4H), 7.33-7.25 (m, 4H),7.25-7.14 (m, 2H), 3.67 (s, 4H), 2.72 (ddt, J=12.3, 7.2, 3.6 Hz, 1H),2.68-2.47 (m, 1H), 2.19-1.94 (m, 4H), 1.62 (qd, J=12.6, 3.2 Hz, 2H),1.38 (qd, J=12.8, 3.1 Hz, 2H).

trans-N,N-dibenzyl-4-[2-(difluoromethyl)triazol-4-yl]cyclohexanamine

To a 100 mL RBF was addedtrans-N,N-dibenzyl-4-(1H-triazol-4-yl)cyclohexanamine (900 mg, 2.6mmol), followed by potassium carbonate (718 mg, 5.2 mmol), and DMF (10mL). Difluoro(iodo)methane (10% wt solution in THF, 5.55 g, 3.12 mmol)was added, and the mixture was stirred at rt overnight. The mixture waspartitioned between EtOAc (150 mL) and water (50 mL), and the layersseparated. The organic layer was washed with water (2×50 mL), and theorganic layer was dried over MgSO₄, filtered, and concentrated underreduced pressure. The crude material was purified by silica gelchromatography (eluent: EtOAc/hexanes, then MeOH/EtOAc) to afford theproduct as an approximately 10:1 mixture of triazole regioisomers(terminal:internal), which were carried through until the end of thesynthetic sequence.

ES/MS: 397.514 (M+H⁺)

trans-4-(2-(difluoromethyl)-2H-1,2,3-triazol-4-yl)cyclohexan-1-amine

To 100 mL RBF was addedtrans-N,N-dibenzyl-4-[2-(difluoromethyl)triazol-4-yl]cyclohexanamine(10:1 mixture of terminal:internal triazole isomers) (600 mg, 1.51mmol), and the material was dissolved in ethanol (10 mL). Palladium oncarbon (10% wt, 81 mg) was added, and the reaction was degassed with H₂,then stirred at 35° C. for 72 hours under a hydrogen atmosphere(balloon). The crude mixture was degassed with argon for 1 minute, thenthe solids were removed by filtration through celite. The crude mixturewas concentrated under reduced pressure, and used directly for the nextstep.

6-chloro-4-((trans-4-(2-(difluoromethyl)-2H-1,2,3-triazol-4-yl)cyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide

To a microwave vial was addedtrans-4-(2-(difluoromethyl)-2H-1,2,3-triazol-4-yl)cyclohexan-1-amine(209 mg, 0.966 mmol),4,6-dichloro-N-[(2R)-2-fluoro-3-hydroxy-3-methyl-butyl]pyridine-3-carboxamide(190 mg, 0.644 mmol) (prepared in an identical fashion to Example 42,step 1), and NMP (2 mL). N,N-Diisopropylethylamine (0.28 mL, 1.61 mL)was added, and the vial was sealed and heated at 150° C. in a microwavereactor for 1 hour. The crude mixture was dissolved in EtOAc (50 mL),then washed once with water (20 mL), and once with brine (20 mL). Theorganic layer was dried over MgSO₄, filtered, and concentrated underreduced pressure. The crude material was purified by silica gelchromatography (eluent: EtOAc/hexanes, then MeOH/EtOAc).

ES/MS: 475.605 (M+H⁺)

6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-[[4-[2-(difluoromethyl)triazol-4-yl]cyclohexyl]amino]-N-[(2R)-2-fluoro-3-hydroxy-3-methyl-butyl]pyridine-3-carboxamide(75)

6-chloro-4-((trans-4-(2-(difluoromethyl)-2H-1,2,3-triazol-4-yl)cyclohexyl)amino)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(10:1 terminal:internal mixture of triazole isomers) (0.1 g, 0.211 mmol)and7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrileI-1 (0.80 g, 0.295 mmol) were added to a microwave vial followed by DME(1.0 mL), XPhos Pd G3 (23.8 mg, 0.0316 mmol) and K₃PO₄ (0.5M in water,0.842 mL, 0.421 mmol). The resulting mixture was purged with argon for30 seconds, sealed and heated to 120° C. in a microwave reactor for 20minutes. The reaction mixture was filtered and purified by RP-HPLC(eluent: water/MeCN*0.1% TFA) to afford the product as a 10:1 mixture ofterminal:internal triazole isomers. The desired internal triazole isomerwas separated by SFC (IC column, 50% EtOH—NH3). The separated materialwas re-subjected to RP-HPLC (eluent: water/MeCN*0.1% TFA) to afford (75)as a TFA salt.

ES/MS: 582.286 (M+H⁺)

1H NMR (400 MHz, Methanol-d4) δ 8.79 (d, J=2.2 Hz, 1H), 8.72 (d, J=2.2Hz, 1H), 8.61 (s, 1H), 8.23-7.89 (m, 3H), 7.82 (s, 1H), 7.25 (d, J=5.1Hz, 1H), 4.60-4.32 (m, 1H), 4.10-3.71 (m, 2H), 3.63-3.43 (m, 1H),3.24-3.08 (m, 1H), 2.29 (dd, J=47.0, 12.9 Hz, 4H), 1.92-1.60 (m, 4H),1.36-1.25 (m, 6H).

19F NMR (376 MHz, Methanol-d4) δ −98.98 (d, J=57.3 Hz), −194.37-−197.80(m).

Compound Table

The compounds in Table 1 were prepared according to the Examples andProcedures described herein using the appropriate starting materials andprotecting group chemistry as needed.

TABLE 1 Structure # ES/MS m/z Name Procedure

 1 531.3 4-(((1r,4R)-4-(1H-pyrazol-4- yl)cyclohexyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7- yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide  6

 2 531.3 4-(((1s,4S)-4-(1H-pyrazol-4- yl)cyclohexyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7- yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide  6

 3 581.2 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(((1r,4R)-4-(1-(difluoromethyl)-1H-pyrazol-4- yl)cyclohexyl)amino)-N-((R)-2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide  2

 4 599.6 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4- (((1r,4R)-4-(1-(trifluoromethyl)-1H-pyrazol-4- yl)cyclohexyl)amino)nicotinamide  2

 5 595.3 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(((1r,4R)-4-(1-(2,2-difluoroethyl)-1H-pyrazol- 4-yl)cyclohexyl)amino)-N-((R)-2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide  2

 6 613.3 (R)-6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((4-(1- (2,2,2-trifluoroethyl)-1H-pyrazol- 4-yl)cyclohexyl)amino)nicotinamide  1

 7 545.3 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4- (((1r,4R)-4-(1-methyl-1H-pyrazol- 4-yl)cyclohexyl)amino)nicotinamide  4

 8 581.4 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(((1r,4R)-4-(1-(difluoromethyl)-1H-pyrazol-3- yl)cyclohexyl)amino)-N-((R)-2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide  3

 9 595.35 (R)-6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-((4-(1-(difluoromethyl)-3-methyl-1H- pyrazol-4-yl)cyclohexyl)amino)-N-(2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide  1

10 595.38 (R)-6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-((4-(1-(difluoromethyl)-5-methyl-1H- pyrazol-4-yl)cyclohexyl)amino)-N-(2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide  1

11 595.34 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(((1r,4R)-4-(1-(difluoromethyl)-5-methyl-1H- pyrazol-4-yl)cyclohexyl)amino)-N-((R)-2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide  2

12 559.5 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(((1r,4R)-4-(1-ethyl-1H-pyrazol-4- yl)cyclohexyl)amino)-N-((R)-2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide  4

13 585.4 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(((1r,4R)-4-(1-(cyclopropylmethyl)-1H- pyrazol-4-yl)cyclohexyl)amino)-N-((R)-2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide  4

14 571.3 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(((1r,4R)-4-(1-cyclopropyl-1H-pyrazol-4- yl)cyclohexyl)amino)-N-((R)-2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide  4

15 547.3 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4- (((1r,4R)-4-(2-methyl-2H-tetrazol- 5-yl)cyclohexyl)amino)nicotinamide  1

16 547.2 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4- (((1r,4R)-4-(1-methyl-1H-tetrazol- 5-yl)cyclohexyl)amino)nicotinamide  1

17 581.4 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(((1r,4R)-4-(1-(difluoromethyl)-1H-imidazol- 4-yl)cyclohexyl)amino)-N-((R)-2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide  2

18 582.193 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(((1r,4R)-4-(1-(difluoromethyl)-1H-1,2,3- triazol-4-yl)cyclohexyl)amino)-N-((R)-2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide 12

19 546.325 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4- (((1r,4R)-4-(1-methyl-1H-1,2,3- triazol-4-yl)cyclohexyl)amino)nicotinamide 11

20 572.290 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(((1r,4R)-4-(1-cyclopropyl-1H-1,2,3-triazol-4- yl)cyclohexyl)amino)-N-((R)-2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide 10

21 582.34 (R)-6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-((4-(1-(difluoromethyl)-1H-1,2,4-triazol- 3-yl)cyclohexyl)amino)-N-(2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide  1

22 582.56 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(((1r,4R)-4-(1-(difluoromethyl)-1H-1,2,4- triazol-3-yl)cyclohexyl)amino)-N-((R)-2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide  2

23 581.6 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(((1r,4R)-4-(3-(difluoromethyl)-1H-pyrazol-1- yl)cyclohexyl)amino)-N-((R)-2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide  5

24 556.38 4-(((1r,4R)-4-(4-cyano-1H- pyrazol-1-yl)cyclohexyl)amino)-6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-N-((R)-2-fluoro- 3-hydroxy-3-methylbutyl)nicotinamide  5

25 549.27 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(((1r,4R)-4-(4-fluoro-1H-pyrazol-1- yl)cyclohexyl)amino)-N-((R)-2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide  5

26 545.6 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4- (((1r,4R)-4-(4-methyl-1H-pyrazol- 1-yl)cyclohexyl)amino)nicotinamide  5

27 570.3 4-(((1r,4R)-4-(4-(cyanomethyl)- 1H-pyrazol-1-yl)cyclohexyl)amino)-6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide  5

28 581.3 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(((1r,4R)-4-(5-(difluoromethyl)-1H-pyrazol-1- yl)cyclohexyl)amino)-N-((R)-2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide  5

29 631.33 4-(((1r,4R)-4-(3,5- bis(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)amino)-6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide  5

30 599.33 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4- (((1r,4R)-4-(4-(trifluoromethyl)-1H-pyrazol-1- yl)cyclohexyl)amino)nicotinamide  5

31 532.27 4-(((1r,4R)-4-(1H-1,2,3-triazol-1- yl)cyclohexyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7- yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide  1

32 572.23 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(((1r,4R)-4-(4-cyclopropyl-1H-1,2,3-triazol-1- yl)cyclohexyl)amino)-N-((R)-2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide  1

33 588.30 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4- (((1r,4R)-4-(4-(oxetan-3-yl)-1H-1,2,3-triazol-1- yl)cyclohexyl)amino)nicotinamide  1

34 575.20 4-(((1r,4R)-4-(4-carbamoyl-1H- 1,2,3-triazol-1-yl)cyclohexyl)amino)-6-(3- cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide  1

35 582.38 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(((1r,4R)-4-(4-(difluoromethyl)-1H-1,2,3- triazol-1-yl)cyclohexyl)amino)-N-((R)-2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide  1

36 582.31 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(((1r,4R)-4-(3-(difluoromethyl)-1H-1,2,4- triazol-1-yl)cyclohexyl)amino)-N-((R)-2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide  5

37 582.27 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(((1r,4R)-4-(3-(difluoromethyl)-4H-1,2,4- triazol-4-yl)cyclohexyl)amino)-N-((R)-2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide  5

38 533.1 4-(((1r,4R)-4-(1H-tetrazol-1- yl)cyclohexyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7- yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide  1

39 547.3 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4- (((1r,4R)-4-(5-methyl-1,3,4- oxadiazol-2-yl)cyclohexyl)amino)nicotinamide  1

40 577.319 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4- (((1r,4R)-4-(5-(methoxymethyl)-1,3,4-oxadiazol-2- yl)cyclohexyl)amino)nicotinamide  1

41 573.5 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(((1r,4R)-4-(5-cyclopropyl-1,3,4-oxadiazol-2- yl)cyclohexyl)amino)-N-((R)-2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide  1

42 583.4 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(((1r,4R)-4-(5-(difluoromethyl)-1,3,4- oxadiazol-2- yl)cyclohexyl)amino)-N-((R)-2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide  1

43 601.3 (R)-6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-((4-(5-(difluoromethyl)-1,3,4-oxadiazol- 2-yl)-4-fluorocyclohexyl)amino)-N-(2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide  1

44 547.3 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4- (((1r,4R)-4-(5-methyl-1,2,4- oxadiazol-3-yl)cyclohexyl)amino)nicotinamide  1

45 547.3 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4- (((1r,4R)-4-(3-methyl-1,2,4- oxadiazol-5-yl)cyclohexyl)amino)nicotinamide  1

46 582.43 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(((1r,4R)-4-(4-(difluoromethyl)oxazol-2- yl)cyclohexyl)amino)-N-((R)-2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide  2

47 582.4 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(((1r,4R)-4-(3-(difluoromethyl)isoxazol-5- yl)cyclohexyl)amino)-N-((R)-2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide  1

48 546.283 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4- (((1R,3R)-3-(4-methyloxazol-5-yl)cyclohexyl)amino)nicotinamide  1

49 548.241 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4- (((1r,4R)-4-(thiazol-5-yl)cyclohexyl)amino)nicotinamide  2

50 562.195 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4- (((1r,4R)-4-(2-methylthiazol-5-yl)cyclohexyl)amino)nicotinamide  2

51 599.022 (R)-6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-((4-(2-(difluoromethyl)thiazol-5- yl)cyclohexyl)amino)-N-(2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide  1

52 563.3 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4- (((1r,4R)-4-(5-methyl-1,3,4- thiadiazol-2-yl)cyclohexyl)amino)nicotinamide  1

53 599.3 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(((1r,4R)-4-(5-(difluoromethyl)-1,3,4- thiadiazol-2- yl)cyclohexyl)amino)-N-((R)-2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide  1

54 542.24 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4- (((1r,4R)-4-(pyridin-2-yl)cyclohexyl)amino)nicotinamide  2

55 542.267 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4- (((1r,4R)-4-(pyridin-3-yl)cyclohexyl)amino)nicotinamide  2

56 542.268 (R)-6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((4- (pyridin-4-yl)cyclohexyl)amino)nicotinamide  2

57 543.275 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4- (((1r,4R)-4-(pyrimidin-5-yl)cyclohexyl)amino)nicotinamide  2

58 557.27 (R)-6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((4-(2- methylpyrimidin-5-yl)cyclohexyl)amino)nicotinamide  1

59 593.329 (R)-6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-((4-(2-(difluoromethyl)pyrimidin-5- yl)cyclohexyl)amino)-N-(2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide  1

60 573.4 (R)-6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((4-(5- methyl-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1- yl)amino)nicotinamide  1

61 575.31 (R)-4-((4-(1,3,4-thiadiazol-2- yl)bicyclo[2.2.2]octan-1-yl)amino)-6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide  9

62 609.57 (R)-6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-((4-(5-(difluoromethyl)-1,3,4-oxadiazol- 2-yl)bicyclo[2.2.2]octan-1-yl)amino)-N-(2-fluoro-3-hydroxy- 3-methylbutyl)nicotinamide  1

63 585.5 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(((3R,6S)-6-(5-(difluoromethyl)-1,3,4- oxadiazol-2-yl)tetrahydro-2H-pyran-3-yl)amino)-N-((R)-2- fluoro-3-hydroxy-3- methylbutyl)nicotinamide 1

64 575.4 (R)-6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-(5- methyl-1,3,4-oxadiazol-2-yl)-2-oxabicyclo[2.2.2]octan-4- yl)amino)nicotinamide  1

65 611.3 (R)-6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-((1-(5-(difluoromethyl)-1,3,4-oxadiazol- 2-yl)-2-oxabicyclo[2.2.2]octan-4-yl)amino)-N-(2-fluoro-3-hydroxy- 3-methylbutyl)nicotinamide  1

66 558.349 (R)-6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((4- (oxazol-5-yl)bicyclo[2.2.2]octan-1-yl)amino)nicotinamide  1

67 549.5 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4- (((1r,4R)-4-(tetrahydro-2H-pyran- 4-yl)cyclohexyl)amino)nicotinamide  2

68 610.4 (R)-6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-((4-(4,4-difluoropiperidin-1- yl)bicyclo[2.2.2]octan-1-yl)amino)-N-(2-fluoro-3-hydroxy- 3-methylbutyl)nicotinamide  7

69 590.65 (R)-6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((4-(3- oxomorpholino)bicyclo[2.2.2]octan-1-yl)amino)nicotinamide  8

70 531.6 4-(((1r,4R)-4-(1H-pyrazol-3- yl)cyclohexyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7- yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide  2

71 531.6 4-(((1s,4S)-4-(1H-pyrazol-3- yl)cyclohexyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7- yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide  2

72 583.2 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(((1r,4R)-4-(2-(difluoromethyl)-2H-tetrazol-5- yl)cyclohexyl)amino)-N-((R)-2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide  1

73 531.4 (R)-4-((4-(1H-pyrazol-3- yl)cyclohexyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7- yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide  1

74 585.6 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(((3S,6R)-6-(5-(difluoromethyl)-1,3,4- oxadiazol-2-yl)tetrahydro-2H-pyran-3-yl)amino)-N-((R)-2- fluoro-3-hydroxy-3- methylbutyl)nicotinamide 1

75 582.29 6-(3-cyanopyrrolo[1,2- b]pyridazin-7-yl)-4-(((1r,4R)-4-(2-(difluoromethyl)-2H-1,2,3- triazol-4-yl)cyclohexyl)amino)-N-((R)-2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide  11HNMR

Proton NMR data is shown in Table 2.

TABLE 2 Compound 1H-NMR 1 1H NMR (400 MHz, Methanol-d4) δ 8.77 (d, J =2.1 Hz, 1H), 8.69 (d, J = 2.2 Hz, 1H), 8.60 (s, 1H), 8.05 (d, J = 5.1Hz, 1H), 7.93 (s, 1H), 7.57 (s, 2H), 7.23 (d, J = 5.0 Hz, 1H), 4.45(ddd, J = 49.1, 9.4, 2.1 Hz, 1H), 4.10-3.85 (m, 2H), 3.52 (ddd, J =16.0,14.5, 9.4 Hz, 1H), 2.71 (t, J = 11.5 Hz, 1H), 2.38-2.23 (m, 2H),2.24-2.05 (m, 2H), 1.89-1.52 (m, 4H), 1.32 (d, J = 1.7 Hz, 6H),0.97-0.78 (m, 1H). 2 1H NMR (400 MHz, Methanol-d4) δ 8.78 (d, J = 2.2Hz, 1H), 8.69 (d, J = 2.2 Hz, 1H), 8.63 (s, 1H), 8.03 (d, J = 5.1 Hz,1H), 7.90 (s, 1H), 7.56 (s, 2H), 7.24 (d, J = 5.0 Hz, 1H), 4.45 (ddd, J= 49.1, 9.4, 2.2 Hz, 1H), 4.26 (s, 1H), 3.96 (ddd, J = 36.5, 14.5, 2.2Hz, 1H), 3.56-3.42 (m, 1H), 2.82 (t, J = 10.5 Hz, 1H), 2.03 (d, J = 11.0Hz, 7H), 1.77 (d, J = 11.4 Hz, 2H), 1.31 (d, J = 1.7 Hz, 6H), 0.97-0.82(m, 1H). 3 1H NMR (400 MHz, Methanol-d4) δ 8.61-8.57 (m, 2H), 8.55 (d, J= 2.2 Hz, 1H), 8.24 (s, 1H), 7.96 (s, 1H), 7.83 (d, J = 4.8 Hz, 1H),7.72 (s, 1H), 7.43 (t, J = 59.9 Hz, 1H), 7.11 (d, J = 4.9 Hz, 1H), 4.45(ddd, J = 49.0, 9.1, 2.2 Hz, 1H), 3.90 (ddd, J = 35.6, 14.5, 2.3 Hz,1H), 3.70-3.58 (m, 1H), 3.57-3.41 (m, 1H), 2.70 (t, J = 11.8 Hz, 1H),2.36 (d, J = 12.4 Hz, 2H), 2.18 (d, J = 13.2 Hz, 2H), 1.69 (q, J = 11.5Hz, 2H), 1.61-1.44 (m, 2H), 1.32 (d, J = 1.7 Hz, 6H). 4 1H NMR (400 MHz,Methanol-d4) δ 8.78-8.72 (m, 1H), 8.68 (d, J = 1.7 Hz, 1H), 8.57 (s,1H), 8.09-7.96 (m, 2H), 7.91 (s, 1H), 7.81 (s, 1H), 7.21 (dd, J = 5.1,1.6 Hz, 1H), 4.54-4.31 (m, 1H), 4.07-3.83 (m, 2H), 3.59-3.42 (m, 1H),2.80-2.65 (m, 2H), 2.32-2.24 (m, 2H), 2.22-2.12 (m, 2H), 1.81-1.54 (m,4H), 1.29 (d, J = 1.7 Hz, 6H). 5 1H NMR (400 MHz, Methanol-d4) δ 9.04(t, J = 5.5 Hz, 0H), 8.77 (d, J = 2.2 Hz, 1H), 8.69 (d, J = 2.2 Hz, 1H),8.60 (s, 1H), 8.05 (d, J = 5.1 Hz, 1H), 7.93 (s, 1H), 7.59 (s, 1H), 7.51(s, 1H), 7.23 (d, J = 5.1 Hz, 1H), 6.39-5.97 (m, 1H), 4.62-4.33 (m, 4H),4.05-3.83 (m, 3H), 3.52 (ddd, J = 16.1, 14.4, 9.4 Hz, 1H), 2.78-2.61 (m,2H), 2.29 (d, J = 11.5 Hz, 3H), 2.16 (d, J = 12.4 Hz, 3H), 1.82-1.56 (m,6H), 1.32 (d, J = 1.7 Hz, 6H). 6 1H NMR (400 MHz, Methanol-d4) δ 8.60(s, 1H), 8.58 (s, 1H), 8.57-8.55 (m, 2H), 8.50 (t, J = 2.9 Hz, 2H), 8.20(s, 1H), 8.17 (s, 1H), 7.81 (dd, J = 4.8, 1.2 Hz, 2H), 7.66 (d, J = 2.0Hz, 2H), 7.56 (d, J = 5.3 Hz, 2H), 7.09 (d, J = 4.9 Hz, 2H), 4.45 (ddd,J = 48.9, 9.2, 2.3 Hz, 2H), 3.90 (ddd, J = 35.4, 14.7, 2.5 Hz, 3H),3.58-3.41 (m, 1H), 2.76 (s, 1H), 2.66 (t, J = 11.9 Hz, 1H), 2.34 (d, J =12.0 Hz, 2H), 2.16 (d, J = 13.1 Hz, 2H), 1.98 (d, J = 43.0 Hz, 7H),1.85-1.57 (m, 3H), 1.50 (q, J = 11.3 Hz, 2H), 1.31 (dd, J = 3.2, 1.6 Hz,12H). 7 1H NMR (400 MHz, Methanol-d4) δ 9.01 (d, J = 5.9 Hz, 0H), 8.77(d, J = 2.2 Hz, 1H), 8.69 (d, J = 2.1 Hz, 1H), 8.59 (s, 1H), 8.04 (d, J= 5.1 Hz, 1H), 7.92 (s, 1H), 7.48 (s, 1H), 7.41 (s, 1H), 7.23 (d, J =5.1 Hz, 1H), 4.45 (ddd, J = 49.0, 9.4, 2.2 Hz, 1H), 4.12-3.88 (m, 1H),3.87 (s, 3H), 3.69-3.41 (m, 1H), 2.72-2.53 (m, 0H), 2.28 (d, J = 10.9Hz, 2H), 2.15 (d, J = 11.9 Hz, 2H), 1.65 (h, J = 12.0 Hz, 4H), 1.31 (d,J = 1.7 Hz, 6H). 8 1H NMR (400 MHz, Methanol-d4) δ 8.60 (s, 1H), 8.58(d, J = 2.3 Hz, 1H), 8.54 (d, J = 2.2 Hz, 1H), 8.25 (s, 1H), 7.96 (d, J= 2.6 Hz, 1H), 7.83 (d, J = 4.9 Hz, 1H), 7.42 (t, J = 59.9 Hz, 1H), 7.11(d, J = 4.9 Hz, 1H), 6.48 (d, J = 2.7 Hz, 1H), 4.57-4.30 (m, 0H), 3.91(d, J = 52.2 Hz, 0H), 3.37 (s, 3H), 2.83 (s, 1H), 2.37 (d, J = 12.3 Hz,2H), 2.19 (d, J = 13.4 Hz, 2H), 1.79 (d, J = 13.4 Hz, 1H), 1.53 (d, J =12.2 Hz, 1H), 1.32 (d, J = 1.7 Hz, 6H). 9 1H NMR (400 MHz, Methanol-d4)δ 8.75 (d, J = 2.1 Hz, 1H), 8.67 (dd, J = 6.3, 2.2 Hz, 1H), 8.59 (d, J =19.3 Hz, 1H), 8.01 (t, J = 5.7 Hz, 1H), 7.84 (d, J = 25.6 Hz, 2H),7.50-7.06 (m, 2H), 4.62-4.32 (m, 1H), 4.29 (s, 1H), 3.95 (dd, J = 36.3,14.6 Hz, 1H), 3.68-3.36 (m, 1H), 2.70 (t, J = 11.5 Hz, 1H), 2.28 (d, J =3.1 Hz, 3H), 2.08 (d, J = 12.9 Hz, 2H), 2.02-1.85 (m, 4H), 1.67 (q, J =10.9, 9.7 Hz, 2H), 1.29 (d, J = 1.7 Hz, 6H). 10 1H NMR (400 MHz,Methanol-d4) δ 8.84-8.52 (m, 3H), 8.01 (dd, J = 11.0, 5.1 Hz, 1H),7.92-7.81 (m, 1H), 7.58 (d, J = 2.1 Hz, 1H), 7.41 (td, J = 58.6, 1.6 Hz,1H), 7.21 (dd, J = 5.1, 1.8 Hz, 1H), 4.58-4.35 (m, 1H), 4.30 (s, 1H),3.95 (dt, J = 36.6, 14.7 Hz, 1H), 3.54 (ddd, J = 24.6, 16.6, 9.8 Hz,1H), 2.79-2.62 (m, 1H), 2.42 (d, J = 2.7 Hz, 3H), 2.28 (d, J = 11.8 Hz,1H), 2.06 (t, J = 15.6 Hz, 1H), 1.97 (t, J = 14.2 Hz, 2H), 1.89-1.59 (m,4H), 1.30 (dd, J = 4.7, 1.8 Hz, 6H). 11 1H NMR (400 MHz, Methanol-d4) δ8.59 (s, 1H), 8.47 (dd, J = 10.7, 2.3 Hz, 2H), 7.98 (s, 1H), 7.84 (d, J= 4.8 Hz, 1H), 7.61-7.56 (m, 1H), 7.41-7.05 (m, 2H), 4.42 (ddd, J =48.7, 9.0, 2.5 Hz, 1H), 4.17-4.03 (m, 1H), 3.91 (ddd, J = 35.1, 14.6,2.5 Hz, 1H), 3.64-3.43 (m, 1H), 2.61 (dt, J = 10.9, 7.1 Hz, 1H), 2.40(s, 3H), 2.09 (d, J = 13.6 Hz, 2H), 1.98-1.63 (m, 6H), 1.29 (s, 6H).; 1HNMR (400 MHz, Methanol-d4) δ 8.53 (s, 1H), 8.43 (dd, J = 13.9, 2.3 Hz,2H), 8.08 (s, 1H), 7.79 (d, J = 4.7 Hz, 1H), 7.53 (s, 1H), 7.28 (t, J =58.8 Hz, 1H), 7.05 (d, J = 4.8 Hz, 1H), 4.53-4.28 (m, 1H), 3.98-3.79 (m,1H), 3.60 (t, J = 11.5 Hz, 1H), 3.47 (td, J = 15.4, 8.9 Hz, 1H), 2.56(t, J = 11.8 Hz, 1H), 2.40 (s, 3H), 2.33 (d, J = 12.6 Hz, 2H), 1.99 (d,J = 16.4 Hz, 3H), 1.78-1.38 (m, 3H), 1.28 (s, 6H). 12 1H NMR (400 MHz,Methanol-d4) δ 8.77 (d, J = 2.2 Hz, 1H), 8.69 (d, J = 2.1 Hz, 1H), 8.61(s, 1H), 8.05 (d, J = 5.0 Hz, 1H), 7.94 (s, 1H), 7.55 (s, 1H), 7.44 (d,J = 0.8 Hz, 1H), 7.24 (d, J = 5.1 Hz, 1H), 4.46 (ddd, J = 49.0, 9.3, 2.1Hz, 1H), 4.18 (q, J = 7.3 Hz, 2H), 4.07-3.85 (m, 2H), 3.53 (ddd, J =16.1, 14.5, 9.4 Hz, 1H), 3.08 (s, 1H), 2.94 (s, 1H), 2.74-2.57 (m, 1H),2.40-2.23 (m, 2H), 2.22-2.01 (m, 4H), 1.76-1.55 (m, 4H), 1.46 (t, J =7.3 Hz, 3H), 1.32 (d, J = 1.7 Hz, 6H). 13 1H NMR (400 MHz, Methanol-d4)δ 9.03 (t, J = 5.6 Hz, 0H), 8.77 (d, J = 2.2 Hz, 1H), 8.69 (d, J = 2.1Hz, 1H), 8.04 (d, J = 5.1 Hz, 1H), 7.92 (s, 1H), 7.59 (s, 1H), 7.44 (d,J = 0.8 Hz, 1H), 7.23 (d, J = 5.1 Hz, 1H), 4.45 (ddd, J = 49.1, 9.3, 2.1Hz, 1H), 3.98 (d, J = 7.1 Hz, 2H), 3.91 (dd, J = 14.2, 2.6 Hz, 1H),3.58-3.39 (m, 1H), 2.67 (td, J = 11.3, 3.5 Hz, 1H), 2.35-2.09 (m, 4H),1.67 (ddt, J = 21.0, 13.2, 7.4 Hz, 4H), 1.45-1.20 (m, 6H), 0.68-0.51 (m,2H), 0.40 (dt, J = 6.2, 4.6 Hz, 2H). 14 1H NMR (400 MHz, Methanol-d4) δ8.77 (d, J = 2.1 Hz, 1H), 8.69 (d, J = 2.2 Hz, 1H), 8.60 (s, 1H), 8.04(d, J = 5.0 Hz, 1H), 7.93 (s, 1H), 7.58 (s, 1H), 7.43 (d, J = 0.8 Hz,1H), 7.23 (d, J = 5.1 Hz, 1H), 4.45 (ddd, J = 49.1, 9.4, 2.1 Hz, 1H),4.05-3.78 (m, 1H), 3.71-3.41 (m, 2H), 2.64 (td, J = 11.5, 3.9 Hz, 1H),2.31-2.20 (m, 2H), 2.14 (d, J = 11.5 Hz, 2H), 1.80-1.55 (m, 4H), 1.31(d, J = 1.7 Hz, 7H), 1.06 (ddt, J = 8.8, 4.3, 2.4 Hz, 4H). 15 1H NMR(400 MHz, DMSO-d6) δ 8.83 (d, J = 2.3 Hz, 1H), 8.74 (d, J = 2.2 Hz, 1H),8.73 (d, J = 2.7 Hz, 2H), 8.61 (d, J = 7.3 Hz, 1H), 8.16 (s, 1H), 7.84(d, J = 4.8 Hz, 1H), 7.11 (d, J = 4.8 Hz, 1H), 4.85 (s, 1H), 4.38 (ddd,J = 49.2, 9.2, 2.1 Hz, 1H), 4.34 (s, 3H), 3.83-3.59 (m, 1H), 3.59-3.43(m, 0H), 3.47-3.34 (m, 1H), 3.03 (tt, J = 11.8, 3.6 Hz, 1H), 2.20 (dd, J= 26.1, 12.9 Hz, 4H), 1.91-1.68 (m, 2H), 1.49 (q, J = 11.4 Hz, 2H), 1.18(dd, J = 5.6, 1.6 Hz, 6H). 16 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J =2.2 Hz, 1H), 8.76 (d, J = 2.3 Hz, 1H), 8.73 (d, J = 3.1 Hz, 1H), 8.60(d, J = 7.2 Hz, 1H), 8.17 (s, 1H), 7.84 (d, J = 4.8 Hz, 1H), 7.11 (d, J= 4.8 Hz, 1H), 4.85 (s, 1H), 4.38 (ddd, J = 49.3, 9.3, 2.2 Hz, 1H), 4.07(s, 3H), 3.84-3.52 (m, 1H), 3.49-3.35 (m, 1H), 3.21-3.02 (m, 0H), 2.27(d, J = 12.5 Hz, 2H), 2.08 (d, J = 13.2 Hz, 2H), 1.83 (q, J = 12.8 Hz,2H), 1.49 (q, J = 11.6, 11.2 Hz, 2H), 1.18 (dd, J = 5.4, 1.6 Hz, 6H). 171H NMR (400 MHz, Methanol-d4) δ 8.95 (s, 1H), 8.75 (d, J = 2.1 Hz, 1H),8.67 (d, J = 2.1 Hz, 1H), 8.59 (s, 1H), 8.03 (d, J = 5.0 Hz, 1H), 7.95(s, 1H), 7.87-7.51 (m, 2H), 7.21 (d, J = 5.1, 1.5 Hz, 1H), 4.57-4.32 (m,1H), 4.06-3.84 (m, 2H), 3.60-3.41 (m, 1H), 2.97-2.75 (m, 1H), 2.43-2.25(m, 2H), 2.26-2.18 (m, 2H), 1.87-1.72 (m, 2H), 1.70-1.58 (m, 2H), 1.29(d, J = 1.6 Hz, 6H). 18 1H NMR (400 MHz, Methanol-d4) δ 8.77 (d, J = 2.2Hz, 1H), 8.71 (d, J = 2.2 Hz, 1H), 8.59 (s, 1H), 8.32 (s, 1H), 8.14-7.78(m, 3H), 7.24 (d, J = 5.0 Hz, 1H), 4.45 (dd, J = 49.1, 8.4 Hz, 1H), 3.98(dd, J = 23.8, 12.3 Hz, 1H), 3.57-3.44 (m, 2H), 3.04-2.91 (m, 1H),2.36-2.24 (m, 4H), 1.76 (dd, J = 63.9, 12.5 Hz, 4H), 1.36-1.29 (m, 6H).19 1H NMR (400 MHz, Methanol-d4) δ 8.77 (d, J = 2.2 Hz, 1H), 8.70 (d, J= 2.2 Hz, 1H), 8.59 (s, 1H), 8.04 (d, J = 5.0 Hz, 1H), 7.96 (s, 1H),7.77 (s, 1H), 7.23 (d, J = 5.1 Hz, 1H), 4.45 (ddd, J = 49.2, 9.4, 2.1Hz, 1H), 4.10 (s, 3H), 4.02-3.86 (m, 1H), 3.55-3.44 (m, 2H), 2.88 (d, J= 3.5 Hz, 1H), 2.26 (dd, J = 36.9, 12.9 Hz, 4H), 1.90-1.52 (m, 4H),1.35-1.25 (m, 6H). 20 1H NMR (400 MHz, Methanol-d4) δ 8.78 (d, J = 2.2Hz, 1H), 8.71 (d, J = 2.2 Hz, 1H), 8.59 (s, 1H), 8.05 (d, J = 5.1 Hz,1H), 7.97 (s, 1H), 7.85 (s, 1H), 7.24 (d, J = 5.1 Hz, 1H), 4.45 (dd, J =49.1, 7.5 Hz, 1H), 4.07-3.78 (m, 2H), 3.61-3.42 (m, 1H), 2.93-2.79 (m,1H), 2.26 (dd, J = 39.3, 12.9 Hz, 4H), 1.73 (dd, J = 56.0, 12.8 Hz, 4H),1.37-1.27 (m, 6H), 1.27-1.14 (m, 4H). 21 1H NMR (400 MHz, Methanol-d4) δ8.86 (d, J = 7.6 Hz, 1H), 8.75 (t, J = 1.8 Hz, 1H), 8.73-8.63 (m, 1H),8.57 (d, J = 7.2 Hz, 1H), 8.02 (dd, J = 9.5, 5.1 Hz, 1H), 7.90 (d, J =25.7 Hz, 1H), 7.61 (t, J = 59.0 Hz, 1H), 7.27-7.16 (m, 1H), 4.58-4.26(m, 1H), 4.27-3.80 (m, 2H), 3.48 (tdd, J = 15.4, 9.3, 6.3 Hz, 1H),3.16-2.80 (m, 1H), 2.27 (dd, J = 25.8, 13.3 Hz, 2H), 1.97 (ddd, J =64.7, 24.1, 11.9 Hz, 5H), 1.70-1.52 (m, 1H), 1.28 (dd, J = 6.9, 1.7 Hz,6H). 22 1H NMR (400 MHz, Methanol-d4) δ 8.98-8.79 (m, 1H), 8.73 (t, J =1.9 Hz, 1H), 8.66 (dd, J = 3.4, 2.0 Hz, 1H), 8.63-8.51 (m, 1H), 8.02(dd, J = 8.4, 5.1 Hz, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.62 (td, J = 59.1,2.9 Hz, 1H), 7.20 (d, J = 5.0 Hz, 1H), 4.42 (ddt, J = 49.0, 9.3, 2.7 Hz,1H), 4.17 (q, J = 4.6, 4.2 Hz, 1H), 3.92 (ddt, J = 36.4, 14.5, 2.1 Hz,1H), 3.70-3.38 (m, 2H), 3.06 (s, 1H), 2.27 (dd, J = 27.4, 13.4 Hz, 1H),2.16-2.04 (m, 3H), 2.03-1.84 (m, 3H), 1.35-1.23 (m, 6H).;1H NMR (400MHz, Methanol-d4) δ 8.81 (d, J = 2.0 Hz, 1H), 8.64-8.49 (m, 3H), 8.06(d, J = 2.1 Hz, 1H), 7.93-7.83 (m, 1H), 7.56 (td, J = 59.1, 2.1 Hz, 1H),7.12 (dd, J = 5.0, 2.1 Hz, 1H), 4.42 (ddd, J = 48.9, 9.3, 2.3 Hz, 1H),3.90 (ddd, J = 35.9, 14.5, 2.4 Hz, 1H), 3.74 (tq, J = 7.3, 4.3, 3.8 Hz,1H), 3.59-3.43 (m, 1H), 2.91 (tt, J = 12.0, 3.6 Hz, 1H), 2.32 (dd, J =12.8, 3.8 Hz, 2H), 2.23 (dd, J = 13.9, 3.6 Hz, 2H), 1.85 (qd, J = 13.2,3.2 Hz, 2H), 1.57 (qd, J = 12.9, 3.2 Hz, 2H), 1.29 (d, J = 1.8 Hz, 6H).23 1H NMR (400 MHz, Methanol-d4) δ 8.75 (d, J = 2.3 Hz, 1H), 8.69 (d, J= 2.3 Hz, 1H), 8.58 (s, 1H), 8.06 (d, J = 5.0 Hz, 1H), 7.98 (s, 1H),7.58 (d, J = 1.8 Hz, 1H), 7.33-6.89 (m, 2H), 6.63-6.52 (m, 1H),4.57-4.30 (m, 2H), 4.07-3.82 (m, 2H), 3.65-3.43 (m, 1H), 2.47-2.21 (m,4H), 2.13 (d, J = 13.0 Hz, 2H), 1.71 (q, J = 12.4 Hz, 2H), 1.29 (d, J =1.7 Hz, 6H).; 1H NMR (400 MHz, Methanol-d4) δ 8.68 (d, J = 2.1 Hz, 1H),8.59 (d, J = 1.7 Hz, 1H), 8.05 (dd, J = 5.1, 1.7 Hz, 1H), 7.94 (d, J =1.7 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.21 (dd, J = 5.2, 1.6 Hz, 1H),6.73 (td, J = 55.1, 1.7 Hz, 1H), 6.49 (d, J = 2.7 Hz, 1H), 4.58-4.26 (m,2H), 4.08-3.80 (m, 2H), 3.61-3.42 (m, 1H), 2.39-2.30 (m, 2H), 2.25 (d, J= 11.0 Hz, 2H), 2.19-2.03 (m, 2H), 1.71 (qd, J = 12.9, 3.5 Hz, 2H), 1.29(d, J = 1.7 Hz, 6H). 24 1H NMR (400 MHz, Methanol-d4) δ 8.75 (t, J = 2.0Hz, 1H), 8.68 (d, J = 2.2 Hz, 1H), 8.58 (d, J = 1.6 Hz, 1H), 8.35 (d, J= 1.7 Hz, 1H), 8.04 (d, J = 5.1 Hz, 1H), 7.94 (s, 2H), 7.21 (d, J = 5.2Hz, 1H), 4.63-4.31 (m, 2H), 4.08-3.78 (m, 3H), 3.62-3.37 (m, 1H), 2.30(dd, J = 25.8, 12.9 Hz, 4H), 2.15 (dd, J = 14.0, 11.1 Hz, 2H), 1.71 (q,J = 12.4 Hz, 2H), 1.29 (d, J = 1.8 Hz, 6H). 25 1H NMR (400 MHz,Methanol-d4) δ 8.75 (d, J = 2.3 Hz, 1H), 8.69 (d, J = 2.2 Hz, 1H), 8.58(s, 1H), 8.04 (d, J = 5.0 Hz, 1H), 7.95 (s, 1H), 7.76-7.65 (m, 1H),7.51-7.32 (m, 1H), 7.22 (d, J = 5.1 Hz, 1H), 4.42 (ddd, J = 49.0, 9.3,2.3 Hz, 1H), 4.32-4.15 (m, 1H), 4.07-3.80 (m, 2H), 3.49 (ddd, J = 16.1,14.5, 9.3 Hz, 1H), 2.32 (d, J = 12.9 Hz, 2H), 2.23 (d, J = 13.2 Hz, 2H),2.13-1.98 (m, 2H), 1.69 (q, J = 12.9 Hz, 2H), 1.29 (t, J = 1.7 Hz, 6H).26 1H NMR (400 MHz, Methanol-d4) δ 8.75 (d, J = 2.1 Hz, 1H), 8.70 (d, J= 2.2 Hz, 1H), 8.57 (s, 1H), 8.04 (d, J = 5.0 Hz, 1H), 7.96 (s, 1H),7.47 (s, 1H), 7.32 (s, 1H), 7.22 (d, J = 5.0 Hz, 1H), 4.56-4.32 (m, 1H),4.23 (t, J = 11.8 Hz, 1H), 4.07-3.82 (m, 2H), 3.49 (td, J = 15.0, 9.3Hz, 1H), 2.31 (d, J = 12.8 Hz, 2H), 2.20 (d, J = 12.6 Hz, 2H), 2.08 (s,4H), 2.04 (dd, J = 11.5, 1.9 Hz, 1H), 1.69 (q, J = 12.3 Hz, 2H), 1.29(d, J = 1.7 Hz, 6H). 27 1H NMR (400 MHz, Methanol-d4) δ 8.75 (t, J = 1.7Hz, 1H), 8.69 (t, J = 1.8 Hz, 1H), 8.59 (d, J =1.4 Hz, 1H), 8.12-8.02(m, 1H), 7.96 (s, 1H), 7.76 (s, 1H), 7.52 (s, 1H), 7.22 (dd, J = 5.1,1.4 Hz, 1H), 4.58-4.21 (m, 2H), 4.14-3.84 (m, 2H), 3.75 (s, 2H),3.60-3.41 (m, 1H), 2.32 (d, J = 12.9 Hz, 2H), 2.24 (d, J = 13.0 Hz, 2H),2.18-2.06 (m, 2H), 1.81-1.61 (m, 2H), 1.29 (t, J = 1.4 Hz, 6H). 28 1HNMR (400 MHz, Methanol-d4) δ 8.75 (d, J = 2.3 Hz, 1H), 8.69 (d, J = 2.3Hz, 1H), 8.58 (s, 1H), 8.06 (d, J = 5.0 Hz, 1H), 7.98 (s, 1H), 7.58 (d,J = 1.8 Hz, 1H), 7.33-6.89 (m, 2H), 6.63-6.52 (m, 1H), 4.57-4.30 (m,2H), 4.07-3.82 (m, 2H), 3.65-3.43 (m, 1H), 2.47-2.21 (m, 4H), 2.13 (d, J= 13.0 Hz, 2H), 1.71 (q, J = 12.4 Hz, 2H), 1.29 (d, J = 1.7 Hz, 6H).; 1HNMR (400 MHz, Methanol-d4) δ 8.68 (d, J = 2.1 Hz, 1H), 8.59 (d, J = 1.7Hz, 1H), 8.05 (dd, J = 5.1, 1.7 Hz, 1H), 7.94 (d, J = 1.7 Hz, 1H), 7.76(d, J = 2.4 Hz, 1H), 7.21 (dd, J = 5.2, 1.6 Hz, 1H), 6.73 (td, J = 55.1,1.7 Hz, 1H), 6.49 (d, J = 2.7 Hz, 1H), 4.58-4.26 (m, 2H), 4.08-3.80 (m,2H), 3.61-3.42 (m, 1H), 2.39-2.30 (m, 2H), 2.25 (d, J = 11.0 Hz, 2H),2.19-2.03 (m, 2H), 1.71 (qd, J = 12.9, 3.5 Hz, 2H), 1.29 (d, J = 1.7 Hz,6H). 29 1H NMR (400 MHz, Methanol-d4) δ 8.75 (d, J = 2.1 Hz, 1H), 8.67(d, J = 2.1 Hz, 1H), 8.58 (s, 1H), 8.05 (d, J = 5.0 Hz, 1H), 7.91 (s,1H), 7.31-6.58 (m, 4H), 4.56-4.29 (m, 2H), 4.15-3.81 (m, 2H), 3.49 (td,J = 15.2, 9.4 Hz, 1H), 2.48-2.24 (m, 4H), 2.15 (d, J = 12.5 Hz, 2H),1.89-1.60 (m, 2H), 1.29 (d, J = 1.6 Hz, 6H). 30 1H NMR (400 MHz,Methanol-d4) δ 8.75 (d, J = 2.1 Hz, 1H), 8.69 (d, J = 2.2 Hz, 1H), 8.58(s, 1H), 8.18 (s, 1H), 8.04 (d, J = 5.1 Hz, 1H), 7.95 (s, 1H), 7.80 (s,1H), 7.22 (d, J = 5.1 Hz, 1H), 4.60-4.23 (m, 2H), 4.14-3.81 (m, 2H),3.59-3.40 (m, 1H), 2.46-2.21 (m, 4H), 2.14 (dt, J = 14.1, 11.4 Hz, 2H),1.83-1.63 (m, 2H), 1.29 (d, J = 1.6 Hz, 6H). 31 1H NMR (400 MHz,Methanol-d4) δ 8.75 (d, J = 2.2 Hz, 1H), 8.69 (d, J = 2.1 Hz, 1H), 8.62(s, 1H), 8.09-8.05 (m, 2H), 7.96 (s, 1H), 7.77 (d, J = 1.0 Hz, 1H), 7.22(d, J = 5.0 Hz, 1H), 4.71 (tt, J = 11.8, 3.8 Hz, 1H), 4.44 (ddd, J =49.0, 9.3, 2.1 Hz, 1H), 4.10-4.01 (m, 1H), 3.93 (ddd, J = 36.5, 14.6,2.2 Hz, 1H), 3.52 (ddd, J = 16.1, 14.5, 9.4 Hz, 1H), 2.44-2.30 (m, 4H),2.30-2.12 (m, 2H), 1.89-1.67 (m, 2H), 1.30 (d, J = 1.7 Hz, 6H). 32 1HNMR (400 MHz, Methanol-d4) δ 8.76 (d, J = 2.1 Hz, 1H), 8.69 (d, J = 2.2Hz, 1H), 8.59 (s, 1H), 8.05 (d, J = 5.1 Hz, 1H), 7.94 (s, 1H), 7.76 (s,1H), 7.23 (d, J = 5.1 Hz, 1H), 4.58 (tt, J = 11.6, 3.7 Hz, 1H), 4.43(ddd, J = 49.0, 9.3, 2.1 Hz, 1H), 4.06-3.82 (m, 2H), 3.58-3.40 (m, 1H),2.34 (t, J = 12.5 Hz, 4H), 2.24-2.09 (m, 2H), 1.98 (tt, J = 8.5, 5.1 Hz,1H), 1.84-1.65 (m, 2H), 1.30 (d, J = 1.7 Hz, 6H), 1.05-0.94 (m, 2H),0.83-0.71 (m, 2H). j 33 1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J = 2.2Hz, 1H), 8.69 (d, J = 2.2 Hz, 1H), 8.60 (s, 1H), 8.07-8.02 (m, 2H), 7.95(s, 1H), 7.23 (d, J = 5.1 Hz, 1H), 5.16-4.93 (m, 2H), 4.85-4.80 (m, 2H),4.73-4.57 (m, 1H), 4.54-4.32 (m, 2H), 4.12-3.76 (m, 2H), 3.64-3.40 (m,1H), 2.47-2.31 (m, 4H), 2.21 (q, J = 11.6 Hz, 2H), 1.76 (q, J = 11.9 Hz,2H), 1.30 (d, J = 1.6 Hz, 6H). 34 1H NMR (400 MHz, Methanol-d4) δ 8.76(d, J = 2.2 Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.59 (s, 1H), 8.44 (s,1H), 8.06 (d, J = 5.1 Hz, 1H), 7.95 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H),4.80-4.67 (m, 1H), 4.44 (ddd, J = 49.1, 9.4, 2.1 Hz, 1H), 4.12-3.81 (m,2H), 3.62-3.43 (m, 1H), 2.38 (d, J = 11.3 Hz, 4H), 2.29-2.15 (m, 2H),1.87-1.67 (m, 2H), 1.30 (d, J = 1.8 Hz, 6H). 35 1H NMR (400 MHz,Methanol-d4) δ 8.77 (t, J = 1.8 Hz, 1H), 8.72-8.66 (m, 1H), 8.60 (d, J =1.5 Hz, 1H), 8.39 (d, J = 1.6 Hz, 1H), 8.06 (d, J = 5.1 Hz, 1H), 7.95(s, 1H), 7.30-7.18 (m, 1H), 6.98 (t, J = 54.6 Hz, 1H), 4.74 (t, J = 12.4Hz, 1H), 4.58-4.31 (m, 1H), 4.18-3.75 (m, 2H), 3.51 (td, J = 15.1, 9.3Hz, 1H), 2.39 (d, J = 11.6 Hz, 4H), 2.30-2.15 (m, 2H), 1.87-1.64 (m,2H), 1.30 (d, J = 1.6 Hz, 6H). 36 1H NMR (400 MHz, Methanol-d4) δ 8.75(d, J = 2.3 Hz, 1H), 8.68 (d, J = 2.4 Hz, 1H), 8.60 (dd, J = 8.9, 2.4Hz, 2H), 8.05 (t, J = 3.8 Hz, 1H), 7.93 (d, J = 2.5 Hz, 1H), 7.22 (t, J= 3.8 Hz, 1H), 7.03-6.54 (m, 1H), 4.62-4.28 (m, 2H), 4.10-3.81 (m, 2H),3.62-3.41 (m, 1H), 2.33 (t, J = 14.2 Hz, 4H), 2.18 (q, J = 12.8 Hz, 2H),1.73 (q, J = 12.3 Hz, 2H), 1.29 (t, J = 1.6 Hz, 6H). 37 1H NMR (400 MHz,Methanol-d4) δ 8.75 (d, J = 2.3 Hz, 1H), 8.67 (d, J = 2.3 Hz, 1H), 8.58(s, 1H), 8.06 (d, J = 4.8 Hz, 2H), 7.91 (s, 1H), 7.45-6.96 (m, 2H), 4.67(t, J = 11.9 Hz, 1H), 4.56-4.26 (m, 1H), 4.11-3.85 (m, 2H), 3.60-3.43(m, 1H), 2.33 (d, J = 11.0 Hz, 4H), 2.16 (d, J = 12.5 Hz, 2H), 1.73 (q,J = 12.7 Hz, 2H), 1.29 (d, J = 1.8 Hz, 6H). 38 1H NMR (400 MHz,Methanol-d4) δ 9.33 (s, 1H), 8.62 (s, 1H), 8.59 (d, J = 2.2 Hz, 1H),8.56 (d, J = 2.3 Hz, 1H), 8.27 (s, 1H), 7.84 (d, J = 4.8 Hz, 1H), 7.11(d, J = 4.9 Hz, 1H), 5.51 (s, 2H), 4.85-4.73 (m, 1H), 4.46 (ddd, J =48.9, 9.1, 2.3 Hz, 1H), 3.91 (ddd, J = 35.5, 14.5, 2.4 Hz, 1H), 3.76(td, J = 11.4, 9.5, 4.2 Hz, 1H), 3.52 (ddd, J = 16.4, 14.4, 9.2 Hz, 1H),3.37 (s, 1H), 2.45 (t, J = 12.0 Hz, 4H), 2.31-2.10 (m, 2H), 1.79-1.60(m, 2H), 1.32 (d, J = 1.6 Hz, 6H). 39 1H NMR (400 MHz, Methanol-d4) δ8.74 (d, J = 2.2 Hz, 1H), 8.67 (d, J = 2.2 Hz, 1H), 8.58 (s, 1H), 8.03(d, J = 5.0 Hz, 1H), 7.91 (s, 1H), 7.21 (d, J = 5.1 Hz, 1H), 4.42 (ddd,J = 49.1, 9.3, 2.1 Hz, 1H), 4.07-3.82 (m, 2H), 3.63-3.40 (m, 1H),3.11-2.99 (m, 1H), 2.52 (s, 3H), 2.40-2.21 (m, 4H), 1.97-1.79 (m, 2H),1.79-1.53 (m, 2H), 1.29 (d, J = 1.6 Hz, 6H). 40 1H NMR (400 MHz,Methanol-d4) δ 8.74 (d, J = 2.2 Hz, 1H), 8.67 (d, J = 2.2 Hz, 1H), 8.60(s, 1H), 8.04 (d, J = 5.1 Hz, 1H), 7.92 (s, 1H), 7.20 (d, J = 5.1 Hz,1H), 4.43 (ddd, J = 49.1, 9.4, 2.1 Hz, 1H), 4.12-3.82 (m, 2H), 3.63-3.45(m, 1H), 3.30 (p, J = 1.7 Hz, 2H), 3.11 (ddd, J = 12.0, 8.6, 3.4 Hz,1H), 2.49-2.25 (m, 4H), 2.01-1.76 (m, 2H), 1.76-1.56 (m, 2H), 1.29 (d, J= 1.7 Hz, 6H). 41 1H NMR (400 MHz, Methanol-d4) δ 8.75 (d, J = 2.2 Hz,1H), 8.67 (d, J = 2.2 Hz, 1H), 8.58 (s, 1H), 8.03 (d, J = 5.1 Hz, 1H),7.91 (s, 1H), 7.21 (d, J = 5.1 Hz, 1H), 4.42 (ddd, J = 49.1, 9.4, 2.1Hz, 1H), 4.08-3.79 (m, 2H), 3.49 (td, J = 15.2, 9.4 Hz, 1H), 3.08-2.95(m, 1H), 2.40-2.24 (m, 4H), 2.19 (tt, J = 8.4, 5.0 Hz, 1H), 1.94-1.78(m, 2H), 1.76-1.56 (m, 2H), 1.29 (d, J = 1.7 Hz, 6H), 1.24-1.16 (m, 2H),1.11-1.03 (m, 2H). 42 1H NMR (400 MHz, Methanol-d4) δ 8.75 (d, J = 2.2Hz, 1H), 8.67 (d, J = 2.2 Hz, 1H), 8.58 (s, 1H), 8.03 (d, J = 5.0 Hz,1H), 7.91 (s, 1H), 7.21 (d, J = 5.1 Hz, 1H), 7.14 (t, J = 51.6 Hz, 1H),4.42 (ddd, J = 49.0, 9.4, 2.1 Hz, 1H), 4.12-3.79 (m, 2H), 3.63-3.41 (m,1H), 3.26-3.12 (m, 1H), 2.47-2.20 (m, 4H), 2.04-1.84 (m, 2H), 1.76-1.60(m, 2H), 1.29 (d, J = 1.6 Hz, 6H). 43 1H NMR (400 MHz, Methanol-d4) δ8.75 (d, J = 2.2 Hz, 1H), 8.67 (d, J = 2.2 Hz, 1H), 8.60 (s, 1H), 8.03(d, J = 5.0 Hz, 1H), 7.91 (s, 1H), 7.45-7.02 (m, 2H), 4.43 (ddd, J =48.9, 9.3, 2.1 Hz, 1H), 4.17-4.04 (m, 1H), 4.02-3.82 (m, 1H), 3.64-3.38(m, 1H), 2.72-2.51 (m, 2H), 2.48-2.15 (m, 4H), 2.06-1.86 (m, 2H), 1.29(d, J = 1.6 Hz, 6H). 44 1H NMR (400 MHz, Methanol-d4) δ 8.78 (d, J = 2.2Hz, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.60 (s, 1H), 8.06 (d, J = 5.0 Hz,1H), 7.95 (s, 1H), 7.24 (d, J = 5.0 Hz, 1H), 4.45 (ddd, J = 49.1, 9.4,2.1 Hz, 1H), 4.12-3.83 (m, 2H), 3.65-3.44 (m, 1H), 2.94 (s, 1H), 2.61(s, 3H), 2.32 (d, J = 12.7 Hz, 2H), 2.23 (d, J = 13.7 Hz, 2H), 1.88 (s,2H), 1.73-1.59 (m, 2H), 1.32 (d, J = 1.6 Hz, 6H). 45 1H NMR (400 MHz,Methanol-d4) δ 8.74 (d, J = 2.2 Hz, 1H), 8.67 (d, J = 2.2 Hz, 1H), 8.57(s, 1H), 8.03 (d, J = 5.1 Hz, 1H), 7.90 (s, 1H), 7.21 (d, J = 5.1 Hz,1H), 4.42 (ddd, J = 49.1, 9.3, 2.1 Hz, 1H), 4.09-3.83 (m, 2H), 3.64-3.41(m, 1H), 3.18-3.06 (m, 1H), 2.36 (s, 3H), 2.35-2.23 (m, 4H), 2.01-1.82(m, 2H), 1.73-1.58 (m, 2H), 1.29 (d, J = 1.7 Hz, 6H). 46 1H NMR (400MHz, Methanol-d4) δ 8.63-8.49 (m, 3H), 8.29-8.07 (m, 2H), 7.82 (dd, J =5.7, 2.5 Hz, 1H), 7.08 (d, J = 4.9 Hz, 1H), 6.98-6.56 (m, 1H), 4.64-4.46(m, 1H), 4.43-4.30 (m, 1H), 4.02-3.79 (m, 1H), 3.78-3.58 (m, 1H), 3.48(td, J = 16.2, 15.6, 8.6 Hz, 1H), 2.99 (dd, J = 13.8, 9.0 Hz, 1H), 2.31(dd, J = 29.0, 13.0 Hz, 3H), 1.86 (q, J = 12.9 Hz, 2H), 1.66-1.43 (m,1H), 1.36-1.25 (m, 6H).; 1H NMR (400 MHz, Methanol-d4) δ 8.75 (d, J =2.2 Hz, 1H), 8.66 (d, J = 2.2 Hz, 1H), 8.59 (s, 1H), 8.21-8.08 (m, 1H),8.01 (d, J = 5.1 Hz, 1H), 7.87 (d, J = 2.9 Hz, 1H), 7.21 (d, J = 5.1 Hz,1H), 6.76 (t, J = 54.3 Hz, 1H), 4.41 (ddd, J = 49.1, 9.3, 2.2 Hz, 1H),4.16 (s, 1H), 4.05-3.82 (m, 1H), 3.48 (td, J = 15.8, 15.4, 9.4 Hz, 1H),3.14 (d, J = 11.6 Hz, 1H), 2.21-1.85 (m, 10H), 1.27 (d, J = 1.8 Hz, 6H).47 1H NMR (400 MHz, Methanol-d4) δ 8.77 (d, J = 2.2 Hz, 1H), 8.70 (d, J= 2.1 Hz, 1H), 8.60 (s, 1H), 8.06 (d, J = 5.1 Hz, 1H), 7.92 (s, 1H),7.24 (d, J = 5.1 Hz, 1H), 6.93 (t, J = 53.7 Hz, 1H), 6.51 (s, 1H), 4.45(ddd, J = 49.0, 9.4, 2.2 Hz, 1H), 4.08-3.81 (m, 2H), 3.63-3.42 (m, 1H),3.11-2.99 (m, 1H), 2.49-2.19 (m, 4H), 1.95-1.77 (m, 2H), 1.75-1.60 (m,2H), 1.32 (d, J = 1.7 Hz, 6H). 48 1H NMR (400 MHz, Methanol-d4) δ 8.77(d, J = 2.2 Hz, 1H), 8.74 (d, J = 1.8 Hz, 1H), 8.68 (d, J = 2.3 Hz, 1H),8.15-7.89 (m, 2H), 7.23 (dd, J = 5.3, 1.8 Hz, 1H), 5.29 (t, J = 3.8 Hz,1H), 4.44 (ddd, J = 49.0, 9.4, 2.3 Hz, 1H), 4.08-3.79 (m, 3H), 3.56 (d,J = 1.7 Hz, 3H), 1.29 (d, J = 1.9 Hz, 6H). 49 1H NMR (400 MHz,Methanol-d4) δ 8.90 (s, 1H), 8.74 (d, J = 2.1 Hz, 1H), 8.67 (d, J = 2.2Hz, 1H), 8.62 (s, 0H), 8.57 (s, 1H), 8.03 (d, J = 5.1 Hz, 1H), 7.88 (s,1H), 7.73 (s, 1H), 7.21 (d, J = 5.1 Hz, 1H), 4.49 (dd, J = 9.4, 2.1 Hz,1H), 4.36 (dd, J = 9.3, 2.1 Hz, 1H), 4.27 (s, 0H), 3.95 (s, 0H), 3.49(dd, J = 9.4, 1.5 Hz, 0H), 3.11 (s, 0H), 2.22 (s, 1H), 2.05 (t, J = 14.9Hz, 1H), 1.81 (q, J = 12.3 Hz, 2H), 1.73-1.59 (m, 2H), 1.43 (d, J = 10.3Hz, 0H), 1.29 (d, J = 1.7 Hz, 6H). 50 1H NMR (400 MHz, Methanol-d4) δ8.31 (s, 1H), 8.01 (s, 1H), 7.97-7.69 (m, 2H), 7.28 (d, J = 5.2 Hz, 1H),7.14 (s, 1H), 6.81 (s, 1H), 6.48 (s, 1H), 3.86-3.56 (m, 1H), 3.53 (s,1H), 3.36-3.04 (m, 1H), 2.79 (d, J = 14.0 Hz, 1H), 2.41 (s, 1H),2.12-1.81 (m, 3H), 1.52 (dd, J = 29.9, 12.1 Hz, 1H), 1.33 (d, J = 19.4Hz, 5H), 1.07 (s, 2H), 0.93 (s, 0H), 0.64-0.42 (m, 6H). 51 1H NMR (400MHz, Methanol-d4) δ 8.74 (d, J = 2.2 Hz, 1H), 8.65 (d, J = 2.3 Hz, 1H),8.61 (s, 1H), 7.99 (d, J = 5.1 Hz, 1H), 7.88 (s, 1H), 7.75 (s, 1H), 7.20(d, J = 5.0 Hz, 1H), 7.11-6.77 (m, 1H), 4.55-4.34 (m, 1H), 4.27 (s, 1H),3.95 (dd, J = 36.4, 14.6 Hz, 1H), 3.52 (td, J = 14.2, 13.4, 8.3 Hz, 1H),3.24 (s, 1H), 2.06 (dt, J = 30.8, 13.8 Hz, 6H), 1.84 (d, J = 12.0 Hz,2H), 1.29 (d, J = 1.8 Hz, 6H). 52 — 53 1H NMR (400 MHz, Methanol-d4) δ8.75 (d, J = 2.1 Hz, 1H), 8.68 (d, J = 2.2 Hz, 1H), 8.58 (s, 1H), 8.04(d, J = 5.1 Hz, 1H), 7.91 (s, 1H), 7.48-7.06 (m, 2H), 4.58-4.31 (m, 1H),4.15-3.82 (m, 2H), 3.60-3.36 (m, 2H), 2.59-2.21 (m, 4H), 2.07-1.87 (m,2H), 1.81-1.61 (m, 2H), 1.29 (d, J = 1.4 Hz, 6H). 54 1H NMR (400 MHz,Methanol-d4) δ 8.85-8.77 (m, 1H), 8.75 (d, J = 2.2 Hz, 1H), 8.71 (d, J =5.6 Hz, 1H), 8.67 (d, J = 2.2 Hz, 1H), 8.60 (s, 1H), 8.58-8.50 (m, 1H),8.12-7.90 (m, 3H), 7.22 (d, J = 5.0 Hz, 1H), 4.49 (dd, J = 9.4, 2.1 Hz,0H), 4.37 (dd, J = 9.4, 2.2 Hz, 0H), 4.08-3.79 (m, 2H), 3.60-3.42 (m,0H), 2.99 (s, 0H), 2.35 (s, 1H), 2.14 (d, J = 13.1 Hz, 2H), 1.89 (d, J =13.1 Hz, 1H), 1.71 (s, 1H), 1.28 (dd, J = 13.1, 1.7 Hz, 6H). 55 1H NMR(400 MHz, Methanol-d4) δ 8.75 (d, J = 2.2 Hz, 1H), 8.68 (d, J = 2.2 Hz,1H), 8.62 (d, J = 6.8 Hz, 2H), 8.25 (dd, J = 8.6, 6.9 Hz, 1H), 8.12-7.91(m, 3H), 7.73-7.58 (m, 1H), 7.21 (d, J = 5.0 Hz, 1H), 6.77 (s, 1H), 4.45(dd, J = 9.4, 2.2 Hz, 1H), 4.33 (dd, J = 9.3, 2.1 Hz, 0H), 4.02-3.75 (m,1H), 3.48 (td, J = 15.6, 9.8 Hz, 1H), 3.12 (s, 0H), 2.95 (d, J = 19.1Hz, 1H), 2.79 (t, J = 18.6 Hz, 2H), 2.62-2.45 (m, 1H), 2.40-2.20 (m,1H), 2.13 (p, J = 6.8 Hz, 1H), 1.94 (s, 0H), 1.62-1.35 (m, 0H), 1.26 (d,J = 1.7 Hz, 6H). 56 1H NMR (400 MHz, Methanol-d4) δ 8.84-8.70 (m, 3H),8.70-8.62 (m, 2H), 8.05 (dd, J = 13.0, 5.5 Hz, 3H), 7.90 (s, 1H), 7.21(d, J = 5.1 Hz, 1H), 4.60-4.23 (m, 2H), 3.92 (ddd, J = 36.1, 14.5, 2.2Hz, 1H), 3.76-3.52 (m, 1H), 3.44 (t, J = 7.1 Hz, 1H), 3.23-3.05 (m, 2H),2.35 (t, J = 8.1 Hz, 1H), 2.25-2.11 (m, 2H), 2.10-1.96 (m, 5H), 1.86 (q,J = 13.0 Hz, 2H), 1.30 (d, J = 1.6 Hz, 6H). 57 1H NMR (400 MHz,Methanol-d4) δ 9.05 (s, 1H), 8.80 (s, 2H), 8.74 (d, J = 2.1 Hz, 1H),8.70-8.63 (m, 2H), 8.59 (s, 0H), 8.02 (dd, J = 8.1, 5.0 Hz, 1H), 7.91(d, J = 18.6 Hz, 1H), 7.21 (dd, J = 5.1, 2.0 Hz, 1H), 4.50 (td, J = 8.8,2.2 Hz, 1H), 4.46-4.29 (m, 1H), 4.09-3.82 (m, 1H), 3.54 (dddd, J = 31.1,16.1, 14.5, 9.4 Hz, 1H), 2.85 (d, J = 29.2 Hz, 1H), 2.34 (d, J = 12.6Hz, 1H), 2.24-1.75 (m, 6H), 1.73-1.59 (m, 1H), 1.40-1.21 (m, 6H). 58 1HNMR (400 MHz, Methanol-d4) δ 8.75 (s, 1H), 8.66 (d, J = 4.1 Hz, 2H),8.60 (d, J = 23.2 Hz, 1H), 8.01 (s, 0H), 7.90 (d, J = 16.2 Hz, 1H), 7.21(d, J = 5.1 Hz, 1H), 4.50 (td, J = 8.8, 2.2 Hz, 1H), 4.46-4.29 (m, 1H),4.09-3.82 (m, 1H), 3.54 (dddd, J = 31.1, 16.1, 14.5, 9.4 Hz, 1H), 2.85(d, J = 29.2 Hz, 1H), 2.34 (d, J = 12.6 Hz, 1H), 2.24-1.75 (m, 6H),1.73-1.59 (m, 1H), 2.67 (d, J = 2.2 Hz, 3H), 1.30 (d, J = 4.8 Hz, 6H).59 1H NMR (400 MHz, Methanol-d4) δ 8.89 (d, J = 2.7 Hz, 2H), 8.75 (d, J= 2.4 Hz, 1H), 8.72-8.63 (m, 1H), 8.11-7.97 (m, 1H), 7.91 (dd, J = 18.8,2.6 Hz, 1H), 7.21 (dd, J = 5.1, 2.2 Hz, 1H), 7.08-6.83 (m, 1H), 6.66(dd, J = 54.4, 3.3 Hz, 1H), 4.63-4.32 (m, 1H), 4.18-3.83 (m, 2H),3.71-3.42 (m, 1H), 3.03-2.81 (m, 1H), 2.35 (d, J = 12.6 Hz, 1H),2.22-1.78 (m, 7H), 1.69 (q, J = 12.3 Hz, 1H), 1.30 (dd, J = 5.1, 1.8 Hz,6H). 60 1H NMR (400 MHz, Methanol-d4) δ 8.81-8.69 (m, 2H), 8.56 (s, 1H),8.36 (s, 1H), 7.95 (d, J = 5.1 Hz, 1H), 7.22 (d, J = 5.1 Hz, 1H), 4.41(ddd, J = 49.1, 9.4, 2.1 Hz, 1H), 3.92 (ddd, J = 36.4, 14.6, 2.1 Hz,1H), 3.63-3.39 (m, 1H), 2.52 (s, 3H), 2.25 (d, J = 4.8 Hz, 12H), 1.28(d, J = 1.7 Hz, 6H). 61 1H NMR (400 MHz, Methanol-d4) δ 9.38 (s, 1H),8.80-8.73 (m, 2H), 8.56 (s, 1H), 8.39 (s, 1H), 7.95 (d, J = 5.1 Hz, 1H),7.22 (d, J = 5.1 Hz, 1H), 4.58-4.27 (m, 1H), 3.92 (ddd, J = 36.6, 14.6,2.1 Hz, 1H), 3.48 (td, J = 15.7, 9.4 Hz, 1H), 2.32 (s, 12H), 1.28 (d, J= 1.6 Hz, 6H). 62 1H NMR (400 MHz, Methanol-d4) δ 8.75 (d, J = 2.1 Hz,2H), 8.58 (d, J = 2.1 Hz, 1H), 8.35 (s, 1H), 7.96 (d, J = 4.9 Hz, 1H),7.29-6.92 (m, 2H), 4.41 (ddd, J = 49.1, 9.4, 2.2 Hz, 1H), 3.91 (ddd, J =36.5, 14.6, 2.2 Hz, 1H), 3.49 (td, J = 15.1,9.3 Hz, 1H), 2.30 (s, 12H),1.28 (d, J = 1.8 Hz, 6H). 63 1H NMR (400 MHz, Methanol-d4) δ 8.75 (d, J= 2.2 Hz, 1H), 8.67 (d, J = 2.2 Hz, 1H), 8.62 (s, 1H), 8.06 (d, J = 5.0Hz, 1H), 7.95 (s, 1H), 7.44-7.02 (m, 2H), 5.02 (dd, J = 9.2, 3.6 Hz,1H), 4.43 (ddd, J = 49.0, 9.1, 2.3 Hz, 1H), 4.30-4.14 (m, 2H), 3.94(ddd, J = 36.4, 14.7, 2.7 Hz, 1H), 3.77-3.59 (m, 1H), 3.60-3.42 (m, 1H),2.52-2.39 (m, 1H), 2.37-2.19 (m, 2H), 2.06-1.88 (m, 1H), 1.30 (q, J =1.8 Hz, 6H). 64 1H NMR (400 MHz, Methanol-d4) δ 8.75 (q, J = 2.2 Hz,2H), 8.61 (s, 1H), 8.35 (s, 1H), 7.96 (d, J = 5.0 Hz, 1H), 7.22 (d, J =5.1 Hz, 1H), 4.55-4.27 (m, 3H), 3.92 (ddd, J = 36.5, 14.6, 2.1 Hz, 1H),3.49 (ddd, J = 16.0, 14.5, 9.4 Hz, 1H), 2.63 (t, J = 7.9 Hz, 2H), 2.55(s, 3H), 2.51-2.30 (m, 6H), 1.28 (d, J = 1.6 Hz, 6H). 65 1H NMR (400MHz, Methanol-d4) δ 8.76 (d, J = 1.6 Hz, 2H), 8.62 (d, J = 1.1 Hz, 1H),8.33 (s, 1H), 7.97 (d, J = 5.2 Hz, 1H), 7.22 (d, J = 5.2 Hz, 1H), 7.17(t, J = 51.4 Hz, 1H), 4.58-4.30 (m, 3H), 4.04-3.80 (m, 1H), 3.60-3.42(m, 1H), 2.67 (m, 2H), 2.47 (m, 6H), 1.29 (d, J = 1.4 Hz, 6H). 66 1H NMR(400 MHz, Methanol-d4) δ 8.80-8.74 (m, 2H), 8.58 (s, 1H), 8.37 (s, 1H),8.14 (s, 1H), 7.97 (d, J = 5.0 Hz, 1H), 7.25 (d, J = 5.1 Hz, 1H), 6.89(s, 1H), 4.44 (ddd, J = 49.0, 9.4, 2.1 Hz, 1H), 3.95 (ddd, J = 36.8,14.5, 2.1 Hz, 1H), 3.58-3.42 (m, 1H), 2.33-2.24 (m, 6H), 2.21-2.11 (m,6H), 1.33-1.29 (m, 6H). 67 1H NMR (400 MHz, Methanol-d4) δ 8.74 (d, J =2.2 Hz, 1H), 8.65 (d, J = 2.2 Hz, 1H), 8.55 (s, 1H), 8.00 (d, J = 5.0Hz, 1H), 7.85 (s, 1H), 7.20 (d, J = 5.0 Hz, 1H), 4.41 (ddd, J = 49.0,9.3, 2.1 Hz, 1H), 4.07-3.84 (m, 3H), 3.84-3.71 (m, 1H), 3.57-3.43 (m,1H), 3.40 (t, J = 11.0 Hz, 2H), 2.22 (d, J = 12.2 Hz, 2H), 1.96 (d, J =12.1 Hz, 2H), 1.68 (d, J = 11.1 Hz, 2H), 1.53-1.15 (m, 14H). 68 1H NMR(400 MHz, Methanol-d4) δ 8.76 (s, 2H), 8.60 (s, 1H), 8.33 (s, 1H), 7.95(d, J = 5.1 Hz, 1H), 7.22 (d, J = 5.0 Hz, 1H), 4.40 (ddd, J = 49.1, 9.4,2.1 Hz, 1H), 4.05-3.33 (m, 5H), 2.42 (d, J = 12.5 Hz, 4H), 2.33 (dd, J =10.0, 5.0 Hz, 6H), 2.22 (dd, J = 9.9, 5.1 Hz, 6H), 1.28 (d, J = 1.7 Hz,6H). 69 1H NMR (400 MHz, Methanol-d4) δ 8.76 (t, J = 1.5 Hz, 2H), 8.54(s, 1H), 8.41 (s, 1H), 7.92 (d, J = 5.1 Hz, 1H), 7.22 (d, J = 5.1 Hz,1H), 4.40 (ddd, J = 49.0, 9.4, 2.1 Hz, 1H), 4.05 (s, 2H), 4.00-3.87 (m,1H), 3.83 (dd, J = 6.0, 4.1 Hz, 2H), 3.57-3.42 (m, 3H), 2.40 (dd, J =10.3, 5.3 Hz, 6H), 2.24 (dd, J = 10.3, 5.4 Hz, 6H), 1.28 (d, J = 1.7 Hz,6H). Example # 1H-NMR 70 1H NMR (400 MHz, Methanol-d4) δ 8.78 (d, J =2.2 Hz, 1H), 8.70 (d, J = 2.1 Hz, 1H), 8.61 (s, 1H), 8.06 (d, J = 5.1Hz, 1H), 7.96 (s, 1H), 7.69 (d, J = 2.2 Hz, 1H), 7.24 (d, J = 5.0 Hz,1H), 6.33 (d, J = 2.2 Hz, 1H), 4.46 (ddd, J = 49.1, 9.4, 2.1 Hz, 1H),4.14-3.75 (m, 2H), 3.63-3.35 (m, 1H), 2.87 (ddt, J = 12.1, 7.5, 3.7 Hz,1H), 2.32 (dd, J = 12.9, 3.7 Hz, 2H), 2.28-2.12 (m, 2H), 1.74 (dqd, J =65.3, 12.9, 3.2 Hz, 4H), 1.32 (d, J = 1.6 Hz, 7H). 71 1H NMR (400 MHz,Methanol-d4) δ 8.78 (d, J = 2.1 Hz, 1H), 8.69 (d, J = 2.2 Hz, 1H), 8.64(s, 1H), 8.04 (d, J = 5.1 Hz, 1H), 7.91 (s, 1H), 7.67 (d, J = 2.2 Hz,1H), 7.24 (d, J = 5.0 Hz, 1H), 6.92 (dd, J = 6.3, 1.8 Hz, 2H), 6.34 (d,J = 2.2 Hz, 1H), 4.45 (ddd, J = 49.1, 9.4, 2.1 Hz, 1H), 4.27 (s, 1H),4.09-3.89 (m, 2H), 3.79 (d, J = 11.6 Hz, 3H), 3.54 (ddd, J = 15.8, 14.4,9.2 Hz, 1H), 2.99 (t, J = 10.6 Hz, 1H), 2.04 (q, J = 10.9, 9.8 Hz, 7H),1.88 (d, J = 10.0 Hz, 1H), 1.31 (d, J = 1.6 Hz, 7H). 72 1H NMR (400 MHz,Methanol-d4) δ 8.61 (s, 1H), 8.57 (q, J = 2.3 Hz, 2H), 8.28 (s, 1H),8.18 (t, J = 57.0 Hz, 1H), 7.84 (d, J = 4.9 Hz, 1H), 7.11 (d, J = 4.9Hz, 1H), 4.45 (ddd, J = 48.9, 9.1, 2.3 Hz, 1H), 3.90 (ddd, J = 35.5,14.5, 2.3 Hz, 1H), 3.78-3.65 (m, 0H), 3.52 (ddd, J = 16.7, 14.6, 9.1 Hz,1H), 2.44 (d, J = 12.8 Hz, 2H), 2.24 (d, J = 13.4 Hz, 2H), 2.04 (q, J =12.2, 11.7 Hz, 2H), 1.60 (q, J = 12.4 Hz, 2H), 1.32 (d, J = 1.7 Hz, 6H).73 1H NMR (400 MHz, Methanol-d4) δ 9.05 (s, 1H), 8.78 (d, J = 2.2 Hz,2H), 8.62 (d, J = 14.2 Hz, 2H), 8.05 (dd, J = 7.4, 5.1 Hz, 2H), 7.95 (s,1H), 7.90 (s, 1H), 7.65 (d, J = 2.0 Hz, 2H), 7.24 (d, J = 5.1 Hz, 2H),6.31 (dd, J = 8.5, 2.2 Hz, 2H), 4.45 (dd, J = 49.0, 9.3 Hz, 2H), 4.27(s, 1H), 4.05-3.81 (m, 2H), 3.54 (td, J = 16.0, 8.2 Hz, 2H), 2.99 (d, J= 10.7 Hz, 1H), 2.87 (t, J = 12.0 Hz, 0H), 2.32 (d, J = 12.4 Hz, 2H),2.20 (d, J = 13.4 Hz, 2H), 2.05 (d, J = 12.1 Hz, 4H), 1.83 (dt, J =25.9, 11.7 Hz, 3H), 1.65 (q, J = 11.5, 11.1 Hz, 2H), 1.32 (dd, J = 4.1,1.7 Hz, 11H). 74 1H NMR (400 MHz, Methanol-d4) δ 8.75 (d, J = 2.2 Hz,1H), 8.68 (d, J = 2.1 Hz, 1H), 8.62 (s, 1H), 8.06 (d, J = 5.1 Hz, 1H),7.94 (s, 1H), 7.50-7.00 (m, 2H), 5.02 (dd, J = 9.3, 3.5 Hz, 1H),4.55-4.34 (m, 1H), 4.32-4.14 (m, 2H), 4.07-3.85 (m, 1H), 3.66 (dd, J =11.0, 8.4 Hz, 1H), 3.60-3.43 (m, 1H), 2.44 (d, J = 12.7 Hz, 1H),2.39-2.19 (m, 2H), 2.07-1.89 (m, 1H), 1.30 (d, J = 1.6 Hz, 6H). 75 1HNMR (400 MHz, Methanol-d4) δ 8.79 (d, J = 2.2 Hz, 1H), 8.72 (d, J = 2.2Hz, 1H), 8.61 (s, 1H), 8.23-7.89 (m, 3H), 7.82 (s, 1H), 7.25 (d, J = 5.1Hz, 1H), 4.60-4.32 (m, 1H), 4.10-3.71 (m, 2H), 3.63-3.43 (m, 1H),3.24-3.08 (m, 1H), 2.29 (dd, J = 47.0, 12.9 Hz, 4H), 1.92-1.60 (m, 4H),1.36-1.25 (m, 6H).Biological Assays

Biological assays were conducted to measure activity against TNFα andIRAK4. As summarized in Table 3, the test compounds are inhibitors ofIRAK4.

IRAK4 Monocyte TNFα Cell Based Assay Procedure:

Cryopreserved human monocytes (Stem Cell Technologies) were thawed,diluted in RPMI with GlutaMAX™ (Gibco® 200 mM L-alanyl-L-glutamine) (10mM HEPES, 1× Pen-Strep, 55 μM ß-mercaptoethanol, 1 mM Sodium pyruvate)media containing 10% FBS to 0.125×10⁶ cells/ml and recovered at 37° C.for 2 hours. The cell suspension was then plated at a density of 5,000cells/well onto black 384 well Greiner clear bottom plates. Plates werepre-spotted with test compounds and serially diluted in DMSO where 40nL/well were delivered using the Echo 550 acoustic liquid dispenser(Labcyte®) for a final DMSO concentration of 0.1%. Plated cells weretreated with compound for 1 hour at 37° C. Cells were then stimulatedwith 50 pg/ml of LPS (Sigma) excluding outside columns of plate used forunstimulated cell control wells. Cells were incubated for an additional4 hours at 37° C. Cells were then spun out of the media and 5 μl ofsample were taken and analyzed for total TNFα content using the TR-FRETHuman TNFα detection system (CisBio). This system utilizes two labeledantibodies (cryptate and XL665) that bind to two different epitopes ofthe TNFα molecule and produce FRET signal proportional to theconcentration of TNFα in the sample. Detection antibodies are mixed50:50 and 5 μL were dispensed into each well. Plates were covered withclear seals and incubated at room temp overnight. The following morningplates were read using an Envision 2103 Multilabeled reader(PerkinElmer) with excitation/emission/FRET emission at 340 nm/615nm/665 nm, respectively. Fluorescence intensities at 615 nm and 665 nmemission wavelengths were expressed as a ratio (665 nm/615 nm). Percentof control was calculated as follows:%Control=100×(Ratio_(Sample)−Ratio_(0% Stimulation))/(Ratio_(100% Stimulation)−Ratio_(0% Stimulation))

where unstimulated cells (0% stimulation) were the negative control andstimulated cells (100% stimulation) were used as the positive control.

IRAK4 Biochemical Assay Procedure:

IRAK4 enzyme (Carna Biosciences, Chuo-ku, Kobe, Japan) activity wasmeasured by detecting phosphorylated peptide substrate formation usingan antibody against the phosphorylated peptide substrate. This is atime-resolved fluorescence resonance energy transfer (TR-FRET)immunoassay, based on the STK1 KinEASE Assay (Cisbio, Bedford, Mass.).The assay was designed as a simple two-step, endpoint assay (a 5 μlenzyme reaction followed by 5 μl stop and detect Solution) performed inProxiPlate-384 Plus plates (Perkin Elmer, Waltham, Mass.).Staurosporine, a non-selective kinase inhibitor was used as a positivecontrol. Compounds diluted in DMSO were spotted into 384 well platesusing a Labcyte® Echo 550 Liquid Handling System prior to addition ofIRAK4 enzyme and peptide substrate. Reaction solutions were deliveredusing a Multi-Flo (Bio-Tek Instruments). The enzyme and peptide solutionwas incubated with compound for 15 minutes at room temp before thereaction was initiated by the addition of ATP. The standard 5 μlreaction mixture contained 500 μM ATP, 2 μM peptide (STK1 Peptide), 0.75nM of IRAK4 in reaction buffer (50 mM HEPES, pH 7.0, 0.02% NaN₃, 0.01%BSA, 0.1 mM Orthovanadate, 5 mM MgCl₂, 0.025% NP-40, 1 mM DTT). After120 min of incubation at room temperature, 5 μl of Stop and DetectSolution (1:100 Cryptate labeled anti-phosphorylated peptide antibodysolution and 125 nM Tracer in a 50 mM HEPES pH 7.0 detection buffercontaining sufficient EDTA) was added. The plate was then furtherincubated for 60 minutes at room temperature and read on Envision 2103Multilabeled reader (PerkinElmer) with excitation/emission/FRET emissionat 340 nm/615 nm/665 nm, respectively. Fluorescence intensities at 615nm and 665 nm emission wavelengths were expressed as a ratio (665 nm/615nm). Percentage of inhibition was calculated as below:%Inhibition=100×(Ratio_(Sample)−Ratio_(0% Inhibition))/(Ratio_(100% Inhibition)−Ratio_(0% Inhibition))

The 0% inhibition value comes from control wells lacking inhibitor. The100% inhibition value comes from control wells containing a saturatingamount of known inhibitor staurosporine.

TABLE 3 Compound EC50 TNF(nM) IC50 HTRF (nM) 1 4 <1 2 66 <1 3 9 <1 4 373 5 22 <1 6 70 — 7 18 1 8 36 1 9 114 7 10 55 8 11 17 1 12 44 2 13 169 214 53 1 15 35 <1 16 26 <1 17 33 1 18 27 1 19 26 <1 20 49 1 21 60 2 22 672 23 38 1 24 19 <1 25 29 2 26 91 <1 27 58 <1 28 187 2 29 381 7 30 136 431 40 1 32 63 1 33 200 1 34 43 <1 35 16 <1 36 14 <1 37 40 1 38 24 <1 3933 <1 40 66 1 41 38 <1 42 24 <1 43 39 <1 44 28 <1 45 85 2 46 124 2 47 892 48 1050 10 49 13 <1 50 52 1 51 76 3 52 50 1 53 27 <1 54 18 <1 55 25 <156 221 9 57 11 2 58 112 4 59 21 1 60 15 <1 61 4 <1 62 19 <1 63 39 <1 6419 <1 65 23 1 66 8 <1 67 41 1 68 38 <1 69 15 <1 70 27.198 0.822 71205.76 3.129 72 31.321 0.639 73 74 71.436 0.868 75 14.802 0.875

What is claimed is:
 1. A compound of Formula (I):

wherein Y is selected from: —H, —F, —Cl, —Br, —CN, —CF₃, —CF₂H, —OH, and—OCH₃; R¹ is selected from C₃₋₁₀ cycloalkyl optionally substituted withX¹ and 4-12 membered heterocyclyl optionally substituted with X¹;wherein each X¹ is independently oxo, halo, —NO₂, —N₃, —CN, C₁₋₉ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈ haloalkyl, —O—R¹²,—C(O)—R¹², —C(O)O—R¹², —C(O)—N(R¹²)(R¹²), —N(R¹²)(R¹²), —N(R¹²)₂(R¹²)⁺,—N(R¹²)C(O)—R¹², —N(R¹²)C(O)O—R¹², or —N(R¹²)C(O)N(R¹²)(R¹²); wherein“Het” is selected from:

wherein each X² is selected from oxo, halo, N₃, —CN, C₁₋₉ alkyl, C₃₋₆cycloalkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈ haloalkyl,4-12 membered heterocyclyl —O—R¹², C₁₋₆ cyano alkyl, C₁₋₆ alkyl ether,—OC(O)R¹², —OC(O)OR¹², —OC(O)—N(R¹²)(R¹²), and —C(O)N(R¹²)(R¹²), whereinany alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, or heterocyclyl isoptionally substituted with Z^(1a); R² is selected from: a) C₁₋₁₀ alkyloptionally substituted with Z¹; b) C₃₋₁₀ cycloalkyl optionallysubstituted with Z¹; c) 5-10 membered heteroaryl optionally substitutedwith Z¹; d) C₆₋₁₀ aryl optionally substituted with Z¹; and e) 4-12membered heterocyclyl optionally substituted with Z¹; wherein Z¹ isindependently oxo, halo, —NO₂, —N₃, —CN, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈ haloalkyl, aryl, heteroaryl,heterocyclyl, —O—R¹², —C(O)—R¹², —C(O)O—R¹², —C(O)—N(R¹²)(R¹²),—N(R¹²)(R¹²), —N(R¹²)₂(R¹²)⁺, —N(R¹²)C(O)—R¹², —N(R¹²)C(O)O—R¹²,—N(R¹²)C(O)N(R¹²)(R¹²), —N(R¹²)S(O)₂(R¹²), —NR¹²S(O)₂N(R¹²)(R¹²),—NR¹²S(O)₂O(R¹²), —OC(O)R¹², —OC(O)OR¹², —OC(O)—N(R¹²)(R¹²), —Si(R¹²)₃,—S—R¹², —S(O)R¹², —S(O)(NH)R¹², —S(O)₂R¹² or —S(O)₂N(R¹²)(R¹²); whereinany alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, heteroaryl orheterocyclyl is optionally substituted with Z^(1a); each Z^(1a) isindependently oxo, halo, —NO₂, —CN, —N₃, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈ haloalkyl, aryl, heteroaryl,heterocyclyl, —O—R¹², —C(O)R¹², —C(O)O—R¹², —C(O)N(R¹²)(R¹²),—N(R¹²)(R¹²), —N(R¹²)₂(R¹²)⁺, —N(R¹²)—C(O)R¹², —N(R¹²)C(O)O(R¹²),—N(R¹²)C(O)N(R¹²)(R¹²), —N(R¹²)S(O)₂(R¹²), —N(R¹²)S(O)₂—N(R¹²)(R¹²),—N(R¹²)S(O)₂O(R¹²), —OC(O)R¹², —OC(O)OR¹², —OC(O)—N(R¹²)(R¹²),—Si(R¹²)₃, —S—R¹², —S(O)R¹², —S(O)(NH)R¹², —S(O)₂R¹² or—S(O)₂N(R¹²)(R¹²); wherein any alkyl, alkenyl, alkynyl, cycloalkyl,haloalkyl, aryl, heteroaryl or heterocyclyl is optionally substitutedwith Z^(1b); each R¹² is independently H, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₅ cycloalkyl, aryl, heteroaryl or heterocyclyl; wherein anyalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl isoptionally substituted with Z^(1a); each Z^(1b) is independently oxo,hydroxy, halo, —NO₂, —N₃, —CN, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₅ cycloalkyl, C₁₋₈ haloalkyl, aryl, heteroaryl, heterocyclyl,—O(C₁₋₉ alkyl), —O(C₂₋₆ alkenyl), —O(C₂₋₆ alkynyl), —O(C₃₋₁₅cycloalkyl), —O(C₁₋₈ haloalkyl), —O(aryl), —O(heteroaryl),—O(heterocyclyl), —NH₂, —NH(C₁₋₉ alkyl), —NH(C₂₋₆ alkenyl), —NH(C₂₋₆alkynyl), —NH(C₃₋₁₅ cycloalkyl), —NH(C₁₋₈ haloalkyl), —NH(aryl),—NH(heteroaryl), —NH(heterocyclyl), —N(C₁₋₉ alkyl)₂, —N(C₃₋₁₅cycloalkyl)₂, —N(C₂₋₆ alkenyl)₂, —N(C₂₋₆ alkynyl)₂, —N(C₃₋₁₅cycloalkyl)₂, —N(C₁₋₈ haloalkyl)₂, —N(aryl)₂, —N(heteroaryl)₂,—N(heterocyclyl)₂, —N(C₁₋₉ alkyl)(C₃₋₁₅ cycloalkyl), —N(C₁₋₉ alkyl)(C₂₋₆alkenyl), —N(C₁₋₉ alkyl)(C₂₋₆ alkynyl), —N(C₁₋₉ alkyl)(C₃₋₁₅cycloalkyl), —N(C₁₋₉ alkyl)(C₁₋₈ haloalkyl), —N(C₁₋₉ alkyl)(aryl),—N(C₁₋₉ alkyl)(heteroaryl), —N(C₁₋₉ alkyl)(heterocyclyl), —C(O)(C₁₋₉alkyl), —C(O)(C₂₋₆ alkenyl), —C(O)(C₂₋₆ alkynyl), —C(O)(C₃₋₁₅cycloalkyl), —C(O)(C₁₋₈ haloalkyl), —C(O)(aryl), —C(O)(heteroaryl),—C(O)(heterocyclyl), —C(O)O(C₁₋₉ alkyl), —C(O)O(C₂₋₆ alkenyl),—C(O)O(C₂₋₆ alkynyl), —C(O)O(C₃₋₁₅ cycloalkyl), —C(O)O(C₁₋₈ haloalkyl),—C(O)O(aryl), —C(O)O(heteroaryl), —C(O)O(heterocyclyl), —C(O)NH₂,—C(O)NH(C₁₋₉ alkyl), —C(O)NH(C₂₋₆ alkenyl), —C(O)NH(C₂₋₆ alkynyl),—C(O)NH(C₃₋₁₅ cycloalkyl), —C(O)NH(C₁₋₈ haloalkyl), —C(O)NH(aryl),—C(O)NH(heteroaryl), —C(O)NH(heterocyclyl), —C(O)N(C₁₋₉ alkyl)₂,—C(O)N(C₃₋₁₅ cycloalkyl)₂, —C(O)N(C₂₋₆ alkenyl)₂, —C(O)N(C₂₋₆ alkynyl)₂,—C(O)N(C₃₋₁₅ cycloalkyl)₂, —C(O)N(C₁₋₈ haloalkyl)₂, —C(O)N(aryl)₂,—C(O)N(heteroaryl)₂, —C(O)N(heterocyclyl)₂, —NHC(O)(C₁₋₉ alkyl),—NHC(O)(C₂₋₆ alkenyl), —NHC(O)(C₂₋₆ alkynyl), —NHC(O)(C₃₋₁₅ cycloalkyl),—NHC(O)(C₁₋₈ haloalkyl), —NHC(O)(aryl), —NHC(O)(heteroaryl),—NHC(O)(heterocyclyl), —NHC(O)O(C₁₋₉ alkyl), —NHC(O)O(C₂₋₆ alkenyl),—NHC(O)O(C₂₋₆ alkynyl), —NHC(O)O(C₃₋₁₅ cycloalkyl), —NHC(O)O(C₁₋₈haloalkyl), —NHC(O)O(aryl), —NHC(O)O(heteroaryl),—NHC(O)O(heterocyclyl), —NHC(O)NH(C₁₋₉ alkyl), —NHC(O)NH(C₂₋₆ alkenyl),—NHC(O)NH(C₂₋₆ alkynyl), —NHC(O)NH(C₃₋₁₅ cycloalkyl), —NHC(O)NH(C₁₋₈haloalkyl), —NHC(O)NH(aryl), —NHC(O)NH(heteroaryl),—NHC(O)NH(heterocyclyl), —SH, —S(C₁₋₉ alkyl), —S(C₂₋₆ alkenyl), —S(C₂₋₆alkynyl), —S(C₃₋₁₅ cycloalkyl), —S(C₁₋₈ haloalkyl), —S(aryl),—S(heteroaryl), —S(heterocyclyl), —NHS(O)(C₁₋₉ alkyl), —N(C₁₋₉alkyl)(S(O)(C₁₋₉ alkyl), —S(O)N(C₁₋₉ alkyl)₂, —S(O)(C₁₋₉ alkyl),—S(O)(NH)(C₁₋₉ alkyl), —S(O)(C₂₋₆ alkenyl), —S(O)(C₂₋₆ alkynyl),—S(O)(C₃₋₁₅ cycloalkyl), —S(O)(C₁ s haloalkyl), —S(O)(aryl),—S(O)(heteroaryl), —S(O)(heterocyclyl), —S(O)₂(C₁₋₉ alkyl), —S(O)₂(C₂₋₆alkenyl), —S(O)₂(C₂₋₆ alkynyl), —S(O)₂(C₃₋₁₅ cycloalkyl), —S(O)₂(C₁₋₈haloalkyl), —S(O)₂(aryl), —S(O)₂(heteroaryl), —S(O)₂(heterocyclyl),—S(O)₂NH(C₁₋₉ alkyl), or —S(O)₂N(C₁₋₉ alkyl)₂; wherein any alkyl,cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substitutedwith one or more halo, C₁₋₉ alkyl, C₁₋₈ haloalkyl, —OH, —NH₂, —NH(C₁₋₉alkyl), —NH(C₃₋₁₅ cycloalkyl), —NH(C₁₋₈ haloalkyl), —NH(aryl),—NH(heteroaryl), —NH(heterocyclyl), —N(C₁₋₉ alkyl)₂, —N(C₃₋₁₅cycloalkyl)₂, —NHC(O)(C₃₋₁₅ cycloalkyl), —NHC(O)(C₁₋₈ haloalkyl),—NHC(O)(aryl), —NHC(O)(heteroaryl), —NHC(O)(heterocyclyl), —NHC(O)O(C₁₋₉alkyl), —NHC(O)O(C₂₋₆ alkynyl), —NHC(O)O(C₃₋₁₅ cycloalkyl),—NHC(O)O(C₁₋₈ haloalkyl), —NHC(O)O(aryl), —NHC(O)O(heteroaryl),—NHC(O)O(heterocyclyl), —NHC(O)NH(C₁₋₉ alkyl), —S(O)(NH)(C₁₋₉ alkyl),S(O)₂(C₁₋₉ alkyl), —S(O)₂(C₃₋₁₅ cycloalkyl), —S(O)₂(C₁₋₈ haloalkyl),—S(O)₂(aryl), —S(O)₂(heteroaryl), —S(O)₂(heterocyclyl), —S(O)₂NH(C₁₋₉alkyl), —S(O)₂N(C₁₋₉ alkyl)₂, —O(C₃₋₁₅ cycloalkyl), —O(C₁₋₈ haloalkyl),—O(aryl), —O(heteroaryl), —O(heterocyclyl), or —O(C₁₋₉ alkyl); or apharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, or deuterated analog thereof.
 2. The compound of claim 1,or a pharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, or deuterated analog thereof, wherein R¹ is 4-12 memberedheterocyclyl optionally substituted with X¹.
 3. The compound of claim 2or a pharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, or deuterated analog thereof, wherein R¹ istetrahydropyran.
 4. The compound of claim 1, or a pharmaceuticallyacceptable salt, stereoisomer, mixture of stereoisomers, or deuteratedanalog thereof, wherein “Het” is substituted with X².
 5. The compound ofclaim 4 or a pharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, or deuterated analog thereof, wherein X² is halo, CN,C₁₋₉ alkyl, C₃₋₆ cycloalkyl, C₃₋₁₅ cycloalkyl, C₁₋₈ haloalkyl, 4-12membered heterocyclyl, —O—R¹², C₁₋₆ cyano alkyl, C₁₋₆ alkyl ether,—OC(O)R¹², —OC(O)OR¹², and —C(O)—N(R¹²)(R¹²).
 6. The compound of claim 4or a pharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomer, or deuterated analog thereof, wherein X² is selected from—F, CN, C₁₋₄ alkyl, C₁₋₈ haloalkyl, C₃₋₄ cycloalkyl, and C₁₋₃cyanoalkyl.7. The compound of claim 4 or a pharmaceutically acceptable salt,stereoisomer, mixture of stereoisomers or deuterated analog thereof,where X² is selected from methyl, ethyl, —CHF₂, —CF₃, cyclopropyl,—CH₂CHF₂, and —CH₂CF₃.
 8. The compound of claim 4 or a pharmaceuticallyacceptable salt, stereoisomer, mixture of stereoisomers or deuteratedanalog thereof, where X² is —CHF₂.
 9. A pharmaceutical compositioncomprising a compound of claim 1, or a pharmaceutically acceptable salt,stereoisomer, mixture of stereoisomers or deuterated analog thereof,together with a pharmaceutically acceptable carrier.
 10. The compound ofclaim 1, represented by a compound of Formula (I):

or a pharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, or deuterated analog thereof, wherein: wherein Y isselected from: —H, —F, —Cl, —Br, —CN, —CF₃, —CF₂H, —OH, and —OCH₃; R¹ isselected from C₃₋₁₀ cycloalkyl optionally substituted with X¹ and 4-12membered heterocyclyl optionally substituted with X¹; wherein each X¹ isindependently oxo, halo, —NO₂, —N₃, —CN, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈ haloalkyl, —O—R¹², —C(O)—R¹²,—C(O)O—R¹², —C(O)—N(R¹²)(R¹²), —N(R¹²)(R¹²), —N(R¹²)₂(R¹²)⁺,—N(R¹²)C(O)—R¹², —N(R¹²)C(O)O—R¹², or —N(R¹²)C(O)N(R¹²)(R¹²); wherein“Het” is selected from:

wherein each X² is selected from oxo, halo, N₃, —CN, C₁₋₉ alkyl, C₃₋₆cycloalkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈ haloalkyl,4-12 membered heterocyclyl —O—R¹², C₁₋₆ cyano alkyl, C₁₋₆ alkyl ether,—OC(O)R¹², —OC(O)OR¹², —OC(O)—N(R¹²)(R¹²), and —C(O)N(R¹²)(R¹²), whereinany alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, or heterocyclyl isoptionally substituted with Z^(1a); R² is selected from: a) C¹⁻¹⁰ alkyloptionally substituted with Z¹; b) C³⁻¹⁰ cycloalkyl optionallysubstituted with Z¹; c) 5−10 membered heteroaryl optionally substitutedwith Z¹; d) C⁶⁻¹⁰ aryl optionally substituted with Z¹; and e) 4−12membered heterocyclyl optionally substituted with Z¹; each Z^(1a) isindependently oxo, halo, —NO₂, —CN, —N₃, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₅ cycloalkyl, C₁₋₈ haloalkyl, aryl, heteroaryl,heterocyclyl, —O—R¹², —C(O)R¹², —C(O)O—R¹², —C(O)N(R¹²)(R¹²),—N(R¹²)(R¹²), —N(R¹²)₂(R¹²)⁺, —N(R¹²)—C(O)R¹², —N(R¹²)C(O)O(R¹²),—N(R¹²)C(O)N(R¹²)(R¹²), —N(R¹²)S(O)₂(R¹²), —N(R¹²)S(O)₂—N(R¹²)(R¹²),—N(R¹²)S(O)₂O(R¹²), —OC(O)R¹², —OC(O)OR¹², —OC(O)—N(R¹²)(R¹²),—Si(R¹²)₃, —S—R¹², —S(O)R¹², —S(O)(NH)R¹², —S(O)₂R¹² or—S(O)₂N(R¹²)(R¹²); wherein any alkyl, alkenyl, alkynyl, cycloalkyl,haloalkyl, aryl, heteroaryl or heterocyclyl is optionally substitutedwith Z^(1b); each R¹² is independently H, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₅ cycloalkyl, aryl, heteroaryl or heterocyclyl; wherein anyalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl isoptionally substituted with Z^(1a); each Z^(1b) is independently oxo,hydroxy, halo, —NO₂, —N₃, —CN, C₁₋₉ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₅ cycloalkyl, C₁₋₈ haloalkyl, aryl, heteroaryl, heterocyclyl,—O(C₁₋₉ alkyl), —O(C₂₋₆ alkenyl), —O(C₂₋₆ alkynyl), —O(C₃₋₁₅cycloalkyl), —O(C₁₋₈ haloalkyl), —O(aryl), —O(heteroaryl),—O(heterocyclyl), —NH₂, —NH(C₁₋₉ alkyl), —NH(C₂₋₆ alkenyl), —NH(C₂₋₆alkynyl), —NH(C₃₋₁₅ cycloalkyl), —NH(C₁₋₈ haloalkyl), —NH(aryl),—NH(heteroaryl), —NH(heterocyclyl), —N(C₁₋₉ alkyl)₂, —N(C₃₋₁₅cycloalkyl)₂, —N(C₂₋₆ alkenyl)₂, —N(C₂₋₆ alkynyl)₂, —N(C₃₋₁₅cycloalkyl)₂, —N(C₁₋₈ haloalkyl)₂, —N(aryl)₂, —N(heteroaryl)₂,—N(heterocyclyl)₂, —N(C₁₋₉ alkyl)(C₃₋₁₅ cycloalkyl), —N(C₁₋₉ alkyl)(C₂₋₆alkenyl), —N(C₁₋₉ alkyl)(C₂₋₆ alkynyl), —N(C₁₋₉ alkyl)(C₃₋₁₅cycloalkyl), —N(C₁₋₉ alkyl)(C₁₋₈ haloalkyl), —N(C₁₋₉ alkyl)(aryl),—N(C₁₋₉ alkyl)(heteroaryl), —N(C₁₋₉ alkyl)(heterocyclyl), —C(O)(C₁₋₉alkyl), —C(O)(C₂₋₆ alkenyl), —C(O)(C₂₋₆ alkynyl), —C(O)(C₃₋₁₅cycloalkyl), —C(O)(C₁₋₈ haloalkyl), —C(O)(aryl), —C(O)(heteroaryl),—C(O)(heterocyclyl), —C(O)O(C₁₋₉ alkyl), —C(O)O(C₂₋₆ alkenyl),—C(O)O(C₂₋₆ alkynyl), —C(O)O(C₃₋₁₅ cycloalkyl), —C(O)O(C₁₋₈ haloalkyl),—C(O)O(aryl), —C(O)O(heteroaryl), —C(O)O(heterocyclyl), —C(O)NH₂,—C(O)NH(C₁₋₉ alkyl), —C(O)NH(C₂₋₆ alkenyl), —C(O)NH(C₂₋₆ alkynyl),—C(O)NH(C₃₋₁₅ cycloalkyl), —C(O)NH(C₁₋₈ haloalkyl), —C(O)NH(aryl),—C(O)NH(heteroaryl), —C(O)NH(heterocyclyl), —C(O)N(C₁₋₉ alkyl)₂,—C(O)N(C₃₋₁₅ cycloalkyl)₂, —C(O)N(C₂₋₆ alkenyl)₂, —C(O)N(C₂₋₆ alkynyl)₂,—C(O)N(C₃₋₁₅ cycloalkyl)₂, —C(O)N(C₁₋₈ haloalkyl)₂, —C(O)N(aryl)₂,—C(O)N(heteroaryl)₂, —C(O)N(heterocyclyl)₂, —NHC(O)(C₁₋₉ alkyl),—NHC(O)(C₂₋₆ alkenyl), —NHC(O)(C₂₋₆ alkynyl), —NHC(O)(C₃₋₁₅ cycloalkyl),—NHC(O)(C₁₋₈ haloalkyl), —NHC(O)(aryl), —NHC(O)(heteroaryl),—NHC(O)(heterocyclyl), —NHC(O)O(C₁₋₉ alkyl), —NHC(O)O(C₂₋₆ alkenyl),—NHC(O)O(C₂₋₆ alkynyl), —NHC(O)O(C₃₋₁₅ cycloalkyl), —NHC(O)O(C₁₋₈haloalkyl), —NHC(O)O(aryl), —NHC(O)O(heteroaryl),—NHC(O)O(heterocyclyl), —NHC(O)NH(C₁₋₉ alkyl), —NHC(O)NH(C₂₋₆ alkenyl),—NHC(O)NH(C₂₋₆ alkynyl), —NHC(O)NH(C₃₋₁₅ cycloalkyl), —NHC(O)NH(C₁₋₈haloalkyl), —NHC(O)NH(aryl), —NHC(O)NH(heteroaryl),—NHC(O)NH(heterocyclyl), —SH, —S(C₁₋₉ alkyl), —S(C₂₋₆ alkenyl), —S(C₂₋₆alkynyl), —S(C₃₋₁₅ cycloalkyl), —S(C₁₋₈ haloalkyl), —S(aryl),—S(heteroaryl), —S(heterocyclyl), —NHS(O)(C₁₋₉ alkyl), —N(C₁₋₉alkyl)(S(O)(C₁₋₉ alkyl), —S(O)N(C₁₋₉ alkyl)₂, —S(O)(C₁₋₉ alkyl),—S(O)(NH)(C₁₋₉ alkyl), —S(O)(C₂₋₆ alkenyl), —S(O)(C₂₋₆ alkynyl),—S(O)(C₃₋₁₅ cycloalkyl), —S(O)(C₁ s haloalkyl), —S(O)(aryl),—S(O)(heteroaryl), —S(O)(heterocyclyl), —S(O)₂(C₁₋₉ alkyl), —S(O)₂(C₂₋₆alkenyl), —S(O)₂(C₂₋₆ alkynyl), —S(O)₂(C₃₋₁₅ cycloalkyl), —S(O)₂(C₁₋₈haloalkyl), —S(O)₂(aryl), —S(O)₂(heteroaryl), —S(O)₂(heterocyclyl),—S(O)₂NH(C₁₋₉ alkyl), or —S(O)₂N(C₁₋₉ alkyl)₂; wherein any alkyl,cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substitutedwith one or more halo, C₁₋₉ alkyl, C₁₋₈ haloalkyl, —OH, —NH₂, —NH(C₁₋₉alkyl), —NH(C₃₋₁₅ cycloalkyl), —NH(C₁₋₈ haloalkyl), —NH(aryl),—NH(heteroaryl), —NH(heterocyclyl), —N(C₁₋₉ alkyl)₂, —N(C₃₋₁₅cycloalkyl)₂, —NHC(O)(C₃₋₁₅ cycloalkyl), —NHC(O)(C₁₋₈ haloalkyl),—NHC(O)(aryl), —NHC(O)(heteroaryl), —NHC(O)(heterocyclyl), —NHC(O)O(C₁₋₉alkyl), —NHC(O)O(C₂₋₆ alkynyl), —NHC(O)O(C₃₋₁₅ cycloalkyl),—NHC(O)O(C₁₋₈ haloalkyl), —NHC(O)O(aryl), —NHC(O)O(heteroaryl),—NHC(O)O(heterocyclyl), —NHC(O)NH(C₁₋₉ alkyl), —S(O)(NH)(C₁₋₉ alkyl),S(O)₂(C₁₋₉ alkyl), —S(O)₂(C₃₋₁₅ cycloalkyl), —S(O)₂(C₁₋₈ haloalkyl),—S(O)₂(aryl), —S(O)₂(heteroaryl), —S(O)₂(heterocyclyl), —S(O)₂NH(C₁₋₉alkyl), —S(O)₂N(C₁₋₉ alkyl)₂, —O(C₃₋₁₅ cycloalkyl), —O(C₁₋₈ haloalkyl),—O(aryl), —O(heteroaryl), —O(heterocyclyl), or —O(C₁₋₉ alkyl); or apharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers, or deuterated analog thereof.